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SUMMARY OF THE 7TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF HIV THERAPY
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John G. Gerber, M.D.
Professor of Medicine and Pharmacology
Divisions of Clinical Pharmacology and Infectious Diseases
University of Colorado Health Sciences Center
Denver, Colorado
TOPICS
Session 1: Clinical Pharmacology in Developing Countries.
-- bioequivalence data of the combination pill of EFV, TDF and FTC
-- pharmacokinetic data on NVP in children in Malawi and Zambia getting the fixed combination tablet Triomune® (d4T+3TC+NVP)
-- simple assay for plasma NVP
-- computer modeling of PK data is to determine early in drug development whether a new drug is a go or no-go
-- EFV pharmacokinetics in subjects from Senegal participating in clinical trials ANRS 1204 and 1206
-- data on NVP in children in Malawi and Zambia getting the fixed combination tablet Triomune®
Session 2. Therapeutic Drug Monitoring
-- utility of GIQ (genotypic inhibitory quotient) in predicting response to therapy
-- an audit of TDM data in UK and Ireland in pediatric patients.
-- pilot data using a computer modeling program (LPPK, multiple model approach to fit patient's data to population PK modeling) to estimate trough concentrations of HIV protease inhibitors in patients using random drug levels based on patient's estimation of the time of last dose
-- computer modeling of PK data is to determine early in drug development whether a new drug is a go or no-go
Session 3: Pharmacokinetics in special patient groups/Toxicity
-- four mechanisms of ARV hepatotoxicity & which patient populations are at high risk to develop them
-- mechanisms of ARV hepatotoxicity and which populations are at high risk to develop them
-- NVP concentrations in subjects with HIV-HCV co-infections vs. HIV alone
-- plasma PK of lamivudine (3TC) in 40 children
Session 4: Pharmacogenetics
-- polymorphism of uridine diphosphate glucuronosyltransferase (UGT) enzymes and their association with the development of atazanavir-induced hyperbilirubinemia.
-- effects of SNPs in the genes encoding for deoxythymidylate kinase (dTMPK) on ZDV-induced changes in hemoglobin concentration
-- genetic variants of the transporters MRP4 and MRP2 and their correlation to tenofovir metabolism and tenofovir elimination
-- utility of abacavir (ABC) patch test in the diagnosis of ABC hypersensitivity.
-- effect of genetic polymorphism in CYP3A4, A5, 2B6, MDR1, MRP1, and BCRP as it correlates to the plasma trough concentration of NVP
Poster Review Session
-- relationship between intragastric pH and ATV bioavailability from subjects participating in previous studies examining the effect of famotidine and omeprazole on the pharmacokinetics of ATV
-- drug-drug interaction between TMC114/r and EFV received significant attention
Roundtable Discussion
significance of the penetration of antiretroviral drugs into sanctuary sites: CNS, genital tract
Session 5: Drug-Drug Interaction
-- drug-drug interaction between tenofovir and their new PI, Brecanavir
-- Gilead demonstrated in in vitro cell lines expressing MRP2 that tenofovir is not a substrate for MRP2 and does not inhibit MRP2, in abstract looking for mechanisms of drug-drug interactions between tenofovir & HIV PIs on a molecular level
-- Kaletra inhibits Pgp equivalently in healthy volunteers and HIV-infected subjects
-- drug-drug interaction between omeprazole and atazanavir/r and fosamprenavir/r when the administration of these drugs was separated by 12 hours
-- PK of methadone after co-administration with steady state Tipranavir/RTV (500/200 mg b.i.d.) in non-methadone using healthy volunteers
Session 6: PK and PD of Existing and New Drugs (1)
-- drug-drug interaction between Brecanavir/RTV (new PI in development) and ATV in HIV-seronegative volunteers
-- PK data with the new NNRTI, BILR-355
-- if there are any differences in the PK of SQV and RTV in seronegative volunteers and HIV-infected subjects and to calculate intrapatient variability in drug concentrations
Session 6: PK and PD of Existing and New Drugs (2)
-- drug interaction between maravoric and TPV/RTV is also very complex
-- effect of CYP3A4 manipulation on the pharmacokinetics of the NNRTI, TMC-278
-- interaction of the new integrase inhibitor (GS-9137) with RTV
The 7th International Workshop on Clinical Pharmacology of HIV Therapy was held on April 20-22 in Lisbon, Portugal. The meeting for the first time attracted 200 attendees which outlined the increasing success and importance of this workshop. The workshop had several quality presentations with clinical relevance that I will review but there were some low points as well. As always all the abstracts and presentations from this meeting can be viewed at www.HIVpresentation.com.
As always this review represents my point of view based on my research and clinical experience in clinical pharmacology and infectious diseases. No single pharmaceutical company supports this summary but I have to disclose that I am or have been a consultant for Roche Pharmaceutical, Bristol-Myers Squibb Pharmaceutical, Agouron/Pfizer Pharmaceutical, Gilead Pharmaceutical, Boehringer-Ingelheim Pharmaceutical, and Tibotec Pharmaceutical.
The meeting began with brief opening remarks by the chairs of the meeting, Drs. Flexner and Burger. Then Dr. Barros presented some epidemiologic data about HIV infection in Portugal. For example, Portugal of all the countries in the European Union has the highest incidence of HIV infection. Portugal has about 30,000 cases of HIV infection with male predominance. Despite full access to medications, the population still experiences 1000 AIDS deaths per year. Lisbon has most of the cases of HIV infection and there is increasing heterosexual transmission of HIV infection. Twenty five percent of pregnant women do not get an HIV test at delivery but only 0.38% of pregnant women are HIV positive.
Dr. Emilia Montero, who was the guest member of the organizing committee this year, presented data on antiretroviral pharmacology collected by her group at the New University of Lisbon. In Lisbon there is increasing interest in collecting TDM data on patients taking HAART. Interestingly most of the drug concentrations (>90%) revolve around efavirenz (EFV) as that is the most commonly used drug in Lisbon as part of the HAART regimen. Observations so far indicate intra-individual variability of EFV concentrations of 29% with no difference in years 1, 2, or 3 after therapy initiation. Inter-individual variability in EFV concentration is 89%. The database did not demonstrate any variation in EFV concentration based on gender or ethnicity. In particular blacks do not have higher EFV concentrations. However aging is associated with higher EFV concentrations. The use of EFV is associated with increasing HDL-Cholesterol levels especially in subjects with low HDL-C at baseline. And finally EFV plasma concentrations were actually slightly lower in patients with HCV and/or HBV co-infection as long as the liver synthetic function was good. However in subjects with severe hepatic insufficiency there was a tendency towards higher concentrations of EFV.
Session 1: Clinical Pharmacology in Developing Countries.
This session began with an invited lecture by Dr. Gary Maartens from South Africa. His presentation concentrated on the priorities for pharmacology research in developing countries. Dr. Maartens identified drug-drug interactions as important in South Africa where there are at least 6 million people with HIV infection in a population of 45 million people. Since tuberculosis and seizure disorder are common concomitant conditions with HIV infection, appropriate therapy for these are important. For tuberculosis rifabutin is not available in South Africa thus rifampin is the important component of TB therapy. Rifampin reduces nevirapine (NVP) concentration 50% an effect that is greater than what is seen with EFV. In children EFV Cmin is reduced by rifampin, but overall children have suboptimal EFV concentrations stressing the importance of better understanding of the antiretroviral drugs in children. In both Africa and Thailand the plasma clearance of NVP and EFV are reduced when compared to Western countries. Thus it would be important to explore pharmacogenetic variability in developing countries in order to optimize antiretroviral therapies.
X Seizures are commonly seen with HIV infection but only phenytoin and barbiturates are available for therapy. These drugs have significant drug-drug interactions with antiretroviral drugs.
X More women are infected with HIV in developing countries. There are limited data and very few adequately powered studies of antiretroviral drugs in pregnancy and children. These studies are sorely needed in order to optimize therapies in these populations. Single dose NVP peripartum should be combined with ZDV+3TC to reduce the development of NNRTI resistance. Overweight women in Africa develop hyperlactatemia with stavudine at 8 times the rate of the general population.
X Drug toxicity is common resulting in substitutions. ZDV discontinuations occur early in <10% of subjects, but stavudine discontinuation occurs later in >10% of subjects on therapy. EFV use has lower drop-outs than NVP use.
X Adherence to therapy is important in Africa as well. There is good correlation between pharmacy refills and survival from HIV in Africa. Adherence rates of 95% or greater result in high level viral suppression. Financial issues related to the affordability of antiretroviral drugs can have a significant effect on adherence.
There were four oral presentations during this session. The most important presentation was by Brian Kearney from Gilead describing for the first time the bioequivalence data of the combination pill of EFV, TDF and FTC (Abstract 82). The results from this study are very important in that for the first time we could have one pill, once daily regimen in the therapy of HIV infection. The simplicity and convenience of this approach will result in improved overall adherence to therapy. In addition this regimen may turn out to be more favorable in terms of resistance in that the half-lives of EFV and tenofovir-diphosphate are quite long so drug monotherapy during any time is unlikely. The data demonstrated bioequivalence of the single pill for all three drugs as compared to administration of the three separate drugs given together. These data were obtained from 45 healthy subjects given a single dose of the combination pill.
These data satisfy the FDA criteria for bioequivalence for all three drugs (90% CI for AUC and Cmax ratio of test product/innovator lies within 0.80 to 1.25)1.
Other oral presentations included data presented by Dr. G. Peytavin on the EFV pharmacokinetics in subjects from Senegal participating in clinical trials ANRS 1204 and 1206 (Abstract 1). These data demonstrated that EFV concentrations were similar in subjects from Senegal to Caucasian subjects from France. In addition there was no gender effect on the PK of EFV. Although 18% of subjects had plasma concentrations above 4 µg/mL (considered toxic), EFV was well tolerated. These data and data from Thailand2 do not suggest that plasma concentrations above 4 µg/mL should be considered toxic and dose adjustments are frequently not necessary.
Dr. R. L'homme presented pharmacokinetic data on NVP in children in Malawi and Zambia getting the fixed combination tablet Triomune® (d4T+3TC+NVP) (Abstract 2). The authors considered NVP trough concentration >3 µg/mL as therapeutic. The dosing of NVP was variable across these 127 HIV-infected children ages 3 months to 16 years. The finding from the study showed that children that received NVP dose of at least 300 mg/mm2/day achieved NVP trough concentrations at least 3 µg/mL consistently (only 3% had concentrations <3 µg/mL) but children receiving half and quarter tablets (50 200 mg/day; median dose 236 mg/mm2/day) were under dosed and 21% had NVP concentrations <3 µg/mL. Children with wasting syndrome tended to have higher plasma concentrations of NVP and very young children had lower concentrations of NVP. Unfortunately the authors did not present any virologic data to correlate plasma concentration to virologic response but these data do suggest that children metabolize NVP more avidly than adults and frequently require adult doses to achieve adult plasma concentration. More work is necessary to understand both the pharmacokinetics of NVP in children and the pharmacokinetic-pharmacodynamic relationship for this drug.
Finally Dr. T. Cressey presented very preliminary data on a simple assay for plasma NVP using a one step immunochromatographic strip test (Abstract 3). The development of an accurate, cheap, and simple plasma assay for antiretroviral drugs for developing countries would be advantageous because of the lack of availability of expensive HPLC equipment that is used in Western countries. Unfortunately the author did not present proper validation in blood for this assay. It is also unclear under which clinical scenario an assay of this kind would be useful.
Session 2: Therapeutic Drug Monitoring
The session started with an invited lecture by Dr. R. Granneman from Abbott Labs describing the use of PK-PD models and simulations in drug development. The goal of computer modeling of PK data is to determine early in drug development whether a new drug is a go or no-go. In the best case scenario a validated model could result in significant cost savings for Pharmaceutical companies. There are numerous components to computer modeling of drug data. The model should be able to answer whether a new drug has acceptable PK variability, frequency of dosing, dose is reasonable for efficacy, and has positive benefit/safety evaluation. In any data simulation drug adherence has to be included in the model. Although the potential for sophisticated computer models is great, the utility of a model requires prospective validation. It was unclear from the talk whether this has been truly accomplished for the computer models Abbott uses in the evaluation of new drug development.
The rest of the session had oral presentations covering various aspects of TDM. Dr. N Helms discussed an automated immunoassay to measure concentrations of atazanavir (ATV) in plasma and CSF with minimal sample preparation and rapid turnaround time (Abstract 10). Roche Diagnostics has been developing sensitive immunoassays for protease inhibitors for several years. Specific antibodies are generated in rabbits. If TDM turns out to be useful in the future, having a simple assay with a rapid turnaround time should be advantageous. The problem is that the utility of TDM in antiretroviral therapy has yet to be demonstrated. There are no prospective studies with clearly positive results. Perhaps this is secondary to design issues or slow turn-around time in reporting the concentrations of drugs. In addition for the combination therapy in HIV infection, using TDM for a single drug may not be the most optimal way of evaluating the adequacy of a regimen.
Dr. M Neely from University of Southern California presented pilot data using a computer modeling program (LPPK, multiple model approach to fit patient's data to population PK modeling) to estimate trough concentrations of HIV protease inhibitors in patients using random drug levels based on patient's estimation of the time of last dose (Abstract 9). 24 patients (5 male and 19 female) were included in this analysis. If an individual's PK parameter did not fit the population PK data, suboptimal adherence was assumed. The study showed that good fit of patient's data to population PK data was associated with a better response rate (defined as HIV-RNA <400 copies/mL) than poor fit of the data. Also achieving "therapeutic concentrations" was always associated with HIV-RNA of <400 copies/mL but sub-therapeutic concentrations did not always result in HIV-RNA >400 copies/mL especially if the subject was taking nelfinavir. These data need to be validated in much larger population and using a prospective approach. In addition the assumption that poor fit of the data results from adherence problems rather the PK outliers needs independent confirmation.
Sara Gibbons from Liverpool, UK presented an audit of TDM data in UK and Ireland in pediatric patients. There were 911 requests for TDM. These concentrations were obtained without documentation of when and if the drug doses were taken. There were several conclusions from the data. The PK variability is greater in children than in adults. There was a tendency to under-dose NVP in children. Adherence appears to be a major issue in children of all age groups. Dr. Gibbons questioned whether the present drug formulations are adequate for children. With increasing numbers of children receiving antiretroviral drugs, understanding the PKPD differences of antiretroviral drugs in children and adults needs to be a priority of the Pharmaceutical companies as drugs are developed in the therapy of HIV infection.
The last two oral presentations as well as a significant part of the TDM Roundtable discussion dealt with the utility of GIQ (genotypic inhibitory quotient) in predicting response to therapy. Rather than discussing individual presentations in detail I would like to make a comment about the use of GIQ in predicting antiretroviral drug response in treatment experienced subjects. It is very difficult for me to be enthusiastic about the use of GIQ as a tool for patient care. When looking across studies that retrospectively evaluated GIQ, several shortcomings become obvious. These studies have variable endpoints. For example abstract 81 by Sheehan et al. defines viral response as achieving HIV-RNA <400 copies/mL or <1000 copies/mL at week 48, while Bonora et al. (Abstract 83) defines viral response as a decrease in HIV-RNA of 1 log and/or achieving HIV-RNA of <50 copies/mL at week 24. All mutations in the protease gene that affect susceptibility to protease inhibitors carry equal weight in GIQ calculation despite the fact that not all mutations result in an equivalent decrease in viral susceptibility. The plasma concentration which is the numerator in the GIQ equation is obtained from trough plasma concentrations drawn without objective documentation of the time the last dose was taken. Thus we have studies with differing endpoints and inconsistent calculations of GIQ. In addition abstract 81 had a total of 27 subjects while abstract 83 had a total of 37 subjects included in the analysis. It is hard to believe that the sample size was considered adequate for any conclusion regarding the effect of GIQ on viral response.
If any of the investigators are serious about finding out if GIQ measurements have any utility in clinical practice they first need to agree on a consistent endpoint and a consistent way to calculate GIQ. Then the investigators need to design a prospective, randomized study that is adequately powered to examine the effect of GIQ utilization vs. standard of care in virologic outcome. If an adequately powered study demonstrates that the use of GIQ is better than the standard of care, then the use of GIQ can be promoted for patient care. I felt that the entire Roundtable discussion on TDM was stacked in favor of TDM by not inviting any investigators having a contrarian view on this subject. It is important to point out that there is not a single study which has demonstrated the utility of TDM in either improving virological outcome or decreasing toxicity with the presently used potent antiretroviral agents. Certainly TDM in the treatment of antiretroviral naive patients is a difficult sell, but for drug experienced patients TDM could have potential utility. However this needs to be demonstrated by prospective, randomized, adequately powered studies. These studies need to weigh efficacy against toxicity as higher concentrations of antiretroviral drugs may be targeted. In addition cost-effectiveness of TDM should be a secondary goal.
Session 3: Pharmacokinetics in special patient groups/Toxicity
This session began with the invited lecture on the hepatotoxicity of antiretroviral drugs (ARV) given by Dr. V. Soriano from Spain. The lecture was an excellent review of the mechanisms of ARV hepatotoxicity and which populations are at high risk to develop them. Dr. Soriano described 4 mechanisms by which ARVs can cause hepatotoxicity. One is mitochondrial toxicity which occurs late and is cumulative secondary to inhibition of mitochondrial DNA synthesis. This is most commonly observed with stavudine and didanosine. Second is a hypersensitivity reaction that is early in onset and likely immune-mediated. Nevirapine and abacavir have been described for this mechanism of hepatotoxicity. Third is direct toxicity which occurs later and certain HIV protease inhibitors are likely culprits. And finally there is the immune reconstititution mechanism not infrequently seen in patients with HCV and HBV co-infection where treatment of HIV infection augments the immune response to HCV and HBV. Underlying HCV co-infection is associated with increased hepatotoxicity to all of the antiretroviral drugs. In particular, HCV genotype 3 is an independent predictor of liver toxicity consisting of microsteatosis, which may be related to a synergistic inhibition of DNA polymerase gamma (mitochondrial DNA polymerase).
NNRTI hepatotoxicity is seen more commonly with NVP than EFV. NVP hepatotoxicity can be fatal and risk factors include high CD4 cell count and female gender. In addition NVP given once a day increases the rate of hepatotoxicity from 8.3% to 13.6%. HCV co-infection and alcohol use also increases the rate of severe hepatotoxicity to NVP. The rate of PI-induced hepatotoxicity is also increased with HCV co-infection. Not all PIs are equally hepatotoxic in that high dose ritonavir (RTV) and tipranavir (TPV) are more hepatotoxic than atazanavir (ATV), nelfinavir, or Kaletra®3. Dr. Soriano concluded that HCV-HIV co-infection results in more rapid progression of HCV infection but antiretroviral drugs can contribute to the hepatoxicity of the underlying viral hepatitis. Therefore less hepatotoxic ARVs should be used in subjects with HIV-HCV co-infection. Examples include the use of EFV over NVP, 3TC and FTC over d4T or ddI, and APV, NFV, Kaletra over TPV and IDV.
There were two oral presentations during this session. Dr. Peytavin reported on the NVP concentrations in subjects with HIV-HCV co-infections vs. HIV alone (Abstract 21). Fibrotest® was used to evaluate fibrosis stage in these subjects. All subjects received NVP b.i.d. The data were reported for 22 HIV/HCV co-infected subjects and 13 HIV-infected subjects. HCV infection had no effect on trough concentration of NVP except in those subjects with advanced fibrosis (F4) where NVP concentrations were significantly higher. Thus in subjects with advanced liver disease secondary to HCV, TDM of NVP may be useful in order to avoid excess plasma concentrations and potential toxicity.
The other oral presentation was by Dr. D. Burger from the Netherlands reporting on the plasma PK of lamivudine (3TC) in 40 children (Abstract 20) receiving the recommended pediatric dose of 4 mg/kg b.i.d.. This dose is twice the adult dose on a mg/kg basis. These investigators found that in subjects age 6 or below the plasma AUCs were 36% lower than in children 7 years and older. The oral plasma clearance per kg was higher in the younger than older children. When the clearance was corrected to body surface area, the difference in clearance was not as apparent. These data suggested that in children lamivudine should be dosed per body surface area rather than weight in order to ensure adequate exposure. These interesting data demonstrate that we still have a lot to learn about antiretroviral pharmacology in children. Dose/kg clearly does not work for developing children as very young children could be consistently under-dosed with their ARVs.
Session 4: Pharmacogenetics
Dr. T Lankisch from Germany (Abstract 30) presented some very interesting data on the polymorphism of uridine diphosphate glucuronosyltransferase (UGT) enzymes and their association with the development of atazanavir-induced hyperbilirubinemia. It is well known that bilirubin glucuronidation is specifically performed by UGT1A1 enzyme, and this enzyme is inhibited by atazanavir and indinavir resulting in unconjugated hyperbilirubinemia. Gilbert's syndrome is associated with a polymorphism in the promoter region of the genes encoding for UGT1A1 (UGT1A1*28). This polymorphism results in decreased UGT1A1 expression. Subjects with Gilbert's syndrome have a greater increase in serum bilirubin when atazanavir is used in HIV therapy. These investigators identified single nucleotide polymorphisms (SNP) in UGT1A1, 1A3, and 1A7 and correlated these SNPs with atazanavir-induced hyperbilirubinemia. The study involved 106 HIV-infected subjects on ATV and 127 healthy donors. Interestingly UGT1A1*28 homozygous variants were seen more commonly in HIV-infected subjects on ATV than in healthy donors. In addition other UGT1A3 and 1A7 variants were also more commonly found in HIV-infected subjects. But most interestingly haplotype with all four SNPs (1A1*28, 1A3-66, 1A7 129/131, 1A7-57) result in severe increase to grade 4 bilirubin elevation on ATV suggesting that other isoforms of UGT may contribute to bilirubin conjugation and are inhibited by ATV.
Dr. S. Mallal from Australia presented data on the effects of SNPs in the genes encoding for deoxythymidylate kinase (dTMPK) on ZDV-induced changes in hemoglobin concentration (Abstract 32). This enzyme is the rate limiting enzyme during ZDV phosphorylation. The investigators found significant variability in dTMPK enzyme and certain haplotypes had higher hemoglobin levels during ZDV administration. But it was unclear how ZDV contributed to the hemoglobin levels since the baseline hemoglobin was different in subjects expressing these haplotypes. In addition the change in hemoglobin during ZDV administration was not different by haplotypes. These data need more work in order to clarify the role of the variability of dTMPK in affecting both ZDV toxicity and ZDV-induced antiviral response.
J Kiser from the University of Colorado (abstract 34) examined the genetic variants of the transporters MRP4 and MRP2 and their correlation to tenofovir metabolism and tenofovir elimination. This was performed in 27 subjects participating in a study examining the effect of Kaletra® on the renal clearance of tenofovir. The study found that cellular concentration of tenofovir-DP was 35% higher in A3463G variant of MRP4 than in the wild type. In addition the variant carrier also had decreased tenofovir renal clearance by 15%. MRP2C-24T variant was associated with increased fractional excretion of tenofovir. Dr. Kiser clearly stated in her conclusions that these data are hypothesis generating and a larger study needs to be performed to confirm these preliminary findings.
Perhaps the most clinically relevant presentation was by Dr. E. Phillips from Canada (abstract 33) on the utility of abacavir (ABC) patch test in the diagnosis of ABC hypersensitivity. ABC hypersensitivity is a clinical diagnosis based on a complex of signs and symptoms but has a false positive rate of 2-3%. Thus some patients may preclude from getting ABC needlessly. Patch test is a reliable marker of hypersensitivity reaction to ABC. A group of patients with a diagnosis of ABC hypersensitivity from four international sites were examined with ABC patch test and the presence of HLA-B*5701, a previously demonstrated genetic marker for ABC hypersensitivity. 23/23 subjects with positive patch test carried HLA-B*5701 while only 2/23 patch test negative subjects carried HLA-B*5701. Interestingly HLA-B*5701 positive subjects with no hypersensitivity reaction to ABC have a variant alcohol dehydrogenase enzyme suggesting that the formation of ABC reactive metabolite may be different in these subjects. Six subjects with history of ABC hypersensitivity but patch test and HLA-B*5701 negative were rechallenged with ABC under close monitoring and did not have a hypersensitivity reaction. The use of ABC patch test and HLA typing may identify subjects that have been falsely labeled as having ABC hypersensitivity. The plan is to expand the oral challenge with ABC in a larger group of subjects with negative patch test and negative HLA-B*5701 but carry a diagnosis of ABC hypersensitivity.
Dr. S. Khoo from Great Britain (abstract 31) presented data regarding the effect of genetic polymorphism in CYP3A4, A5, 2B6, MDR1, MRP1, and BCRP as it correlates to the plasma trough concentration of NVP in 71 HIV-infected subjects (58 males, 13 females) on a NVP-containing regimen. The author found no gender effect in NVP Ctrough in this limited population but CYP2B6 G516T polymorphism was weakly associated with higher NVP Ctrough, similar to what has been described for EFV. However this genetic factor explained only 13% of the NVP Ctrough variability suggesting that environmental factors may play a more important role. Interestingly increasing number of SNPs in these enzymes/transporters was associated with increasing concentrations of NVP. Since presently it is unclear if any of the transporters have a high affinity for NVP, why should genetic polymorphism affect the plasma concentration of NVP?
During the first Poster Review Session by Drs. Kurowski and di Perri several posters were discussed. I will review only the ones that I felt had some clinical relevance.
Abstract 40 by Dr. T. Eley from Bristol-Myers Squibb evaluated the relationship between intragastric pH and ATV bioavailability from subjects participating in previous studies examining the effect of famotidine and omeprazole on the pharmacokinetics of ATV. These studies in healthy volunteers showed that omperazole caused a more profound drop in ATV exposure than famotidine. In fact if famotidine administration was separated from ATV administration by >/= 10 hours, the decrease in ATV exposure was minimal. During the study gastric pH was monitored. When gastric pH was correlated to ATV exposure, it was noticed that gastric pH of 4 was the critical break point for altered PK. If gastric pH was These data demonstrate that omperazole is a more potent inhibitor of gastric acid output and thus affect the PK of ATV more profoundly. In subjects with mild indigestion, H2 blockers are probably adequate for relief but for severe erosive reflux esophagitis, in order for healing to occur, gastric pH has to be close to neutral which can only be achieved with proton pump inhibitors. Thus ATV cannot be used in subjects on proton pump inhibitors.
Abstract 55 dealing with the drug-drug interaction between TMC114/r and EFV received significant attention. The authors reported on the poster that EFV reduced TMC114 AUC by a mean of 13.4% and Cmin by 31.3%. TMC114/r increased EFV AUC by 21% and Cmin by 17%. The conclusion was that there is no clinically significant PK interaction between EFV and TMC114. However during the discussion the variability of EFV induction was brought up. Although the mean decrease in Cmin may not appear to be marked, the variation around the mean may indicate that there are some people who may not achieve adequate concentrations of TMC114. Indeed the 90% CI of LSM ratio was 54.2-87.2% for the Cmin indicating that some subjects had a greater than 50% decrease in Cmin of TMC114 after EFV. The investigators should have defined a priori the percent decrease in drug exposure that would be considered significant. Defining this after data collection seems problematic.
Immediately after the Poster Review Session 1, there was a roundtable discussion regarding the significance of the penetration of antiretroviral drugs into sanctuary sites. This discussion was ably led by Dr. Kashuba from University of North Carolina who has done a lot of work on the pharmacology of antiretroviral drugs in both the male and female genital tract. Dr. Aweeka reviewed some of the data regarding the cerebrospinal (CSF) penetration of antiretroviral drugs. She made it clear from the onset that central nervous system penetration is not equivalent to CSF penetration but this is the best that we can do at the moment. The importance of antiretroviral penetration into sanctuary sites comes to focus if we can demonstrate that viral replication rates and development of drug resistance is compartmentalized. For example if CNS HIV replication can continue despite suppression of viral replication in plasma and lymphatics, then adverse viral effects in CNS can continue despite good peripheral HIV control. In addition, the CNS may become a site for the generation of drug resistant HIV that can eventually reach the blood and lymphatics. Although discordant HIV replication has been infrequently demonstrated in subjects with advanced HIV diseases, it appears from recent data by Letendre et al.4 that CSF penetration of drugs correlates to low HIV-RNA in CSF. What is unclear is whether lower HIV-RNA in CSF secondary to good penetration of drugs is associated with improved central nervous system clinical outcome.
Genital tract penetration of drugs and control of viral replication in the genital tract may be important in the prevention of sexual transmission of HIV. The NRTIs generally penetrate well into male and female genital tracts but drug phosphorylation may not be as active as in peripheral blood mononuclear cells. NNRTIs appear to penetrate into female genital tracts but PI penetration is more inconsistent possibly related to plasma protein binding. There were some interesting discussion points during this important Roundtable. Dr. S. Taylor talked about some data published several years ago showing that NFV and Kaletra® monotherapy for 2 weeks resulted in an equivalent decrease in plasma HIV-RNA, but only Kaletra® reduced CSF HIV-RNA. These data suggest that NFV does not get into the CSF in sufficient quantities to reduce HIV replication (Lafeuillade et al.5). Dr. A. Fridland made the point that since tenofovir prevents vertical transmission of HIV its phosphorylation in the genital tract must be adequate. Dr. A. Kovacs commented that PIs suppress viral replication more effectively in the female genital tract than NNRTIs as demonstrated by persistent genital viral shedding despite suppression of HIV-RNA in plasma with NNRTIs.
Session 5: Drug-Drug Interaction
This session had four very interesting oral presentations. The first was by Dr. S. Ford from GlaxoSmithKline (Abstract 38) dealing with a drug-drug interaction between tenofovir and their new PI, Brecanavir, which has to be administered with RTV. This healthy volunteer study showed that Brecanavir/r increased tenofovir exposure by 32% and Cmax by 24%. This interaction could be explained by the 30% decrease in the renal clearance of tenofovir which decreased from 237 ml/min to 168 ml/min. Part of this decrease in renal clearance of tenofovir was secondary to a decrease in creatinine clearance by 13% when Brecanavir/r was added to tenofovir. Since creatinine has a tubular secretion component, it is unclear whether the decrease in creatinine clearance is a true decrease in GFR (glomerular filtration rate) or a decrease in creatinine secretion. These data are similar to what has been reported at 13th CROI by Dr. J. Kiser6 demonstrating that tenofovir renal clearance is lower in subjects on concomitant Kaletra® as compared to subjects not on a protease inhibitor-containing regimen. Dr. S. Ford suggested that BCV/r inhibition of active tubular secretion of tenofovir via MRP2 transporter may be responsible for this.
Note from Jules Levin: to facilitate your understanding of the report immediately above & the report by author John Gerber immediately below which summarizes abstract 39 here is a little more information from the presentation by A Ray of Gilead. The title of the talk was "Mechanism of Active Tubular Secretion of Tenofocir and Potebtial for a Renal Drug-Drug Interaction with HIV Protease Inhibitors". The issue is that higher tenofovir levels have been observed when Kaletra and tenofovir are used together in a combination suggesting that HIV PIs or RTV-boosted PIs increase tenofovir levels, so why does this occur?
However the next presentation by Dr. A. Ray from Gilead (Abstract 39) elegantly demonstrated in in vitro cell lines expressing MRP2 that tenofovir is not a substrate for MRP2 and does not inhibit MRP2. Tenofovir was not a substrate for Pgp but was a substrate for the MRP4 transporter. However none of the PIs examined inhibited MRP4. The investigators proposed that MRP4 is responsible for the renal tubular secretion of tenofovir. Thus it is unclear why Kaletra® and BCV/r affect the renal elimination of tenofovir. It is certainly possible that another, yet to be identified, transporter is responsible for the tubular secretion of tenofovir which is inhibited by RTV.
These investigators from Gilead had another abstract that was presented as a poster (Abstract 49) showing that the lipophilic tenofovir prodrug, tenofovir disoproxil fumarate, is a substrate for Pgp in Caco2 cell lines, and ATV, LPV, and RTV were able to inhibit Pgp mediated tenofovir disoproxil fumarate efflux. The investigators suggest that the PIs increase tenofovir exposure by the increased intestinal absorption of tenofovir disoproxil fumarate which is rapidly deesterified to tenofovir before reaching systemic circulation. However these experiments do not explain why certain PIs decrease the renal clearance of tenofovir.
Dr. A. Jetter from Cologne, Germany (Abstract 37) presented data showing that Kaletra® inhibits Pgp equivalently in healthy volunteers and HIV-infected subjects as demonstrated by the increase in digoxin exposure by 80% when oral digoxin was co-administered with Kaletra®. Digoxin is a prototype drug for Pgp transporter activity. The authors suggest that the pharmacokinetics of other substrates for Pgp, eg: doxorubicin or verapamil, may be adversely affected by the concomitant use of HIV protease inhibitors.
Finally, Dr. A. Luber from the USA presented data on the drug-drug interaction between omeprazole and atazanavir/r and fosamprenavir/r when the administration of these drugs was separated by 12 hours. In addition, in this healthy volunteer study, omeprazole 20 mg q.d. was utilized which is a dose available over-the-counter in the US. The data showed that omperazole had no effect on the PK of APV but it did reduce ATV exposure. However there was large variability in the effect of omeprazole on ATV exposure in that some volunteers had no measurable interaction while others had a greater than 50% reduction in exposure. Since a priori it is difficult to predict the extent of this interaction in any one individual, the recommendation of not using proton pump inhibitors with ATV/r is valid. If PPI use is absolutely necessary my suggestion is to use either fosAPV/r or Kaletra® in place of ATV/r.
There were several abstracts that were reviewed during the second Poster Discussion Session right after the Drug-Drug Interaction session. I cannot really go over all the data in detail so I will review just a few abstracts that may have clinical interest.
Abstract 42 presented by Dr. J Sabo from Boehringer Ingelheim described the stereoselective PK of methadone after co-administration with steady state Tipranavir/RTV (500/200 mg b.i.d.) in non-methadone using healthy volunteers. Methadone was administered as a single 5 mg dose before and after TPV/RTV, thus the pharmacodynamic response to methadone could not be evaluated. The investigators found that TPV/RTV reduced S-methadone exposure by 63% and R-methadone exposure by 48%. It is the R-methadone that is the active isomer. The authors concluded that this level of decrease is equivalent to what has been described with other PIs. However our own data from ACTG 4017 found that SQV/RTV (400/400 mg b.i.d.) reduced R-methadone exposure by only 32% and part of this reduction was secondary to protein binding displacement as the decrease in unbound R-methadone was only 19%. In our study with chronic methadone using subjects, we did not observe any narcotic withdrawal. The level of decrease in methadone PK by TPV/RTV is 50% which is closer to what is observed with NNRTIs. In addition, it is unclear if there was a protein binding displacement to explain part of the decrease. Therefore, I would be concerned that the administration of TPV/RTV to methadone-using subjects will result in narcotic withdrawal. The safety of TPV/RTV in methadone-using subjects needs to be demonstrated before the use of TPV/RTV can be recommended to ex-IVDU subjects on methadone therapy.
X Abstract 41 showed that TPV/RTV reduces ATV Cmin by 81% making concomitant use of these drugs, as with other PIs and TPV/RTV, impossible.
X There was minimal drug interaction between Brecanavir/r and Kaletra® (Abstract 51).
X The between subject variance in the LPV C12hr for the Kaletra soft gel capsules vs. Kaletra® meltrex tablets was at least twice as great (Abstract 78).
Session 6: PK and PD of Existing and New Drugs (1)
The session began with an invited lecture on "Optimization of Peptide Antagonist of CCR5" given by Dr. Oliver Hartley from Geneva, Switzerland. This was an elegant lecture chronicling the discovery of CCR5 antagonists based on the modification of the chemokine RANTES. The search was for a compound that can be used as a topical microbicide that results in internalization and long term sequestration of the CCR5 receptor. The candidate molecule has to be free of CCR5 signaling because that may increase inflammation and enhance HIV transmission. The affinity for the receptor has to be high because these are peptides and expensive to manufacture in large quantities. After generating a library of compounds, Dr. Hartley described a few analogues of RANTES with high affinity towards the CCR5 receptor, significant receptor internalization but no signal generation. However in general, most pure CCR5 antagonists, as with other cell surface receptors, do not result in receptor internalization. For the basic scientist in the audience, this lecture no doubt generated great interest.
There were 4 oral presentations. The first was by Dr. S. Ford from GlaxoSmithKline describing the drug-drug interaction between Brecanavir/RTV (new PI in development) and ATV in HIV-seronegative volunteers (Abstract 76). When BCV 300 mg/RTV 100 mg given q. 12 hours was combined with ATV 300 mg q.d., the concentrations of ATV were significantly greater than with ATV 300mg/RTV 100 mg alone. The AUC increased by 44%, the Cmax increased by 21%, but the Cmin increased 2.1-fold. Since the dose of RTV was twice the usual dose with ATV and ATV pharmacokinetics are non-linear, it is difficult to conclude whether BCV truly contributed to the increased exposure to ATV. However ATV did increase the AUC, Cmax, and Cmin of BCV by 38%, 48%, and 44%, respectively, consistent with the inhibitory effect of ATV on CYP3A4.
Dr. F. Huang from Boehringer-Ingelheim described PK data with the new NNRTI, BILR-355, that is being developed because the drug retains activity with the usual mutations of the first generation NNRTIs. The drug has a short serum half-life and low trough concentrations when given by itself, but RTV increases the drug's AUC 15-30-fold, and prolongs serum half-life 3-5-fold. The drug even with RTV has to be given twice a day in order to achieve trough concentrations of >200 ng/mL, predicted for efficacy. I have concerns about giving a NNRTI with subtherapeutic doses of RTV unless the target population is already highly PI resistant. With two NNRTIs in advanced development from Tibotec, it is unclear to me how this drug, which has to be given with RTV and twice a day, is going to contribute to HIV therapy.
Dr. L. Dickinson from Liverpool, England presented trough concentration data on SQV and RTV over multiple days collected from two pharmacokinetic studies in seronegative volunteers and HIV-infected subjects (Abstract 60). The purpose of this retrospective analysis was to determine if there are any differences in the PK of SQV and RTV in seronegative volunteers and HIV-infected subjects and to calculate intrapatient variability in drug concentrations. The dose of SQV/RTV was 1000/100 mg b.i.d.. The study found that unlike for ATV, SQV and RTV plasma Ctrough was similar in 10 HIV-infected and 18 seronegative subjects. In addition the intrapatient variability in SQV was 59% which is surprisingly large. Unfortunately the only PK parameter reported was the Ctrough so it is unclear whether other parameters like Cmax and AUC were also similar in the two groups. Nonetheless it is comforting to know that dose ranging studies with SQV/RTV in seronegative volunteers have applicability to HIV-infected subjects.
Finally the last presentation at this session was by Dr. R. Lopez from Barcelona, Spain who examined the feasibility of a limited sampling strategy for ATV in order to estimate an accurate AUC (abstract 84). These investigators used fifty seven 12-hr PK profiles from 50 subjects and used step-wise multiple regression analysis of the data. They found that 8 hr post dose concentration best correlated with ATV AUC, but a limited sampling strategy of 0, 3 hr, and 8 hr after a dose provides 98% accuracy in predicting ATV AUC. A similar analysis was reported at last year's International Workshop on Clinical Pharmacology of HIV Therapy by Regazzi for NFV where a sampling strategy at 0 and 4 hours predicted AUC. Obviously each drug requires its own unique sampling strategy for accurate estimation of the AUC.
Session 6: PK and PD of Existing and New Drugs (2)
This session started with an invited lecture given by Dr. Robert Gross from University of Pennsylvania, USA on HIV Pharmaco-epidemiology. The lecture was an excellent review of the contributions pharmaco-epidemiologic studies can make in recognizing rare drug toxicities, describing new syndromes, and describing drug efficacy in a real world setting. Dr. Gross gave specific examples where rare toxicities were teased out using pharmaco-epidemiologic data. For example identifying the incidence of lactic acidosis in small populations is impossible, but large data sets demonstrated the occurrence rate of <1 per 100 person years, median onset of 4 months, slow resolution, potentially fatal outcome, and concomitant symptoms like fatigue. Also pharmaco-epidemiologic data can correlate rate of adherence to virologic outcome. However there are ongoing challenges in evaluating data sets.
X Multiple drugs are given together; tease apart specific drug effects.
X Recognition of new adverse events; best methods for recognition
X Accuracy issues with adherence measures.
X Appropriate design and reporting of studies
Pharmaco-epidemiology is one way to evaluate the true safety and efficacy of drugs in a real world setting.
There were four oral presentations during this session. Dr. R. van Heeswijk from Tibotec Pharma presented data on the effect of CYP3A4 manipulation on the pharmacokinetics of the NNRTI, TMC-278 (Abstract 74). Basic message is that this drug is metabolized via CYP3A4 because rifampin administration results in an 80% reduction in drug's AUC, and ketoconazole co-administration results in a 49% increase in TMC-278 exposure. TMC-278 had no effect on rifampin and desacetyl rifampin pharmacokinetics but did reduce ketoconazole exposure by 24%. These data point to TMC-278 as a substrate and an inducer of CYP3A.
Dr. S. Abel from Pfizer Global Research and Development presented abstract 59A on the absolute bioavailability of maraviroc after oral and i.v. dosing of the drug, and abstract 77 on the effect of boosted TPV on the pharmacokinetics of maraviroc in HIV seronegative volunteers. Maraviroc is an oral CCR5 antagonist in advanced clinical trials. Maraviroc is a CYP3A4 substrate as well as a Pgp substrate. It does not induce or inhibit any of the CYP isoforms. After oral and i.v. administration, it was determined that the absolute bioavailability of the drug is 23%. The elimination PK of this drug is very complex and based on NONMEM modeling it was determined that a 4-compartment model best describes the i.v. pharmacokinetics of this drug. The terminal half-life of the drug is 13.1 hour which is dependent on the deep compartment kinetics. In simulation experiments, changes in clearance did not result in proportional change in terminal-half life because of the slow diffusion from deep compartment.
The drug interaction between maravoric and TPV/RTV is also very complex. There appears to be no change in Cmax and AUC of maraviroc when used concomitantly with TPV/RTV. This was surprising but no doubt secondary to the opposing effect of TPV/RTV on Pgp and CYP3A. TPV/RTV is a very potent inducer of Pgp but RTV is a potent inhibitor of CYP3A. Although in 12 seronegative subjects this overall effect on maraviroc PK was not changed by TPV/RTV, it is unclear if given to a larger population this finding would remain true. It would be interesting to explore the effect of genetic polymorphisms of Pgp on this interaction. Since two opposing forces are responsible for this neutral drug-drug interaction, I would worry that there may be a subgroup of subjects where TPV/RTV will turn out to be a potent inducer of maraviroc metabolism. We need to be vigilant to this possibility.
Final presentation by Dr. B. Kearney from Gilead Sciences (Abstract 75) described the interaction of the new integrase inhibitor (GS-9137) with RTV. GS-9137 is mostly metabolized via CYP3A4 with glucuronidation being a minor pathway. At steady state RTV increased GS-9137 exposure 20-fold and increased Ctrough 90-fold. RTV also prolonged the terminal half-life from 3.5 hrs to 9.5 hrs. Thus if GS-9137 is combined with RTV the drug can be dosed once daily. However having a suboptimal concentration of a PI may increase the capacity of the virus to generate PI-resistant mutants unless viral replication is completely inhibited by therapy. All three new drugs presented during this session have a promising future in the therapy of antiretroviral-experienced subjects.
The scientific sessions were followed by an FDA Satellite Round Table with the goal being to elucidate the most effective way to present complex drug interaction data in the package insert. There were strong opinions expressed by members of the pharmaceutical industry but it is the practicing clinicians that utilize this information for patient care and their opinions need to be sought.
In summary the 7th International Workshop on Clinical Pharmacology of HIV Therapy had several interesting scientific presentations with clinical relevance. There are three that come to mind. Abstract 82 described the bioequivalence of a single pill containing EFV, TDF, and FTC. We have come far from the days of 12-18 pills a day, given multiple times for an effective HAART regimen. Having a single pill that is given once-a-day for HIV therapy is truly a major advance. Bristol-Myers Squibb and Gilead should be congratulated for collaborating on this important project that makes the lives of HIV-infected people easier. Clearly there will be outliers who will not be able to utilize this fixed dose combination pill. Subjects with renal dysfunction will have the drugs dosed separately because of TDF. The rare subject who metabolizes EFV very slowly (possibly related to CYP2B6 polymorphism) and develops intolerable toxicity as a consequence of high EFV concentrations will also require separate dosing of EFV. But clearly greater than 90% of subjects on an EFV-based regimen will be able to utilize this simple one pill a day regimen which should improve drug adherence and prevent selective drug intake that promotes the development of HIV drug resistance. My prediction is that this single pill will have a favorable impact on maintaining wild-type virus even when drug adherence is not perfect. Abstract 33 which described a potential way to identify subjects who may have been falsely labeled as abacavir hypersensitive was an important study. Abacavir is a potent, generally safe, and well tolerated NRTI which could be available to a subgroup of subjects with the diagnosis of abacavir hypersensitivity if the skin test turns out to be a sensitive and specific test for this identification. And finally the numerous studies on the interaction between tenofovir and RTV-containing PI regimens clarified some of the transporters that are involved in the renal and intestinal transport of tenofovir and tenofovir disoproxil fumarate. Nonetheless still more work needs to be performed in order to clarify through which renal transporter(s) RTV affect the renal secretion of tenofovir.
References:
1. FDA Guidance for Industry. Statistical Approaches to Establishing Bioequivalence. US Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville, MD. 2001.
2. Manosuthia W, Sungkanuparpha S, Thakkinstian A, et al. Efavirenz levels and 24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin. AIDS 2005; 19(14):1481-6.
3. Sulkowski MS. Drug-Induced Liver Injury Associated with Antiretroviral Therapy that Includes HIV-1 Protease Inhibitors. Clin Infec Diseases 2004; 38 (suppl 2):S90-S97.
4. Letendre S, Capparelli E, Best B, et al. Better Antiretroviral Penetration into the Central Nervous System Is Associated with Lower CSF Viral Load. In Program and Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. Feb 5-8, 2006, Denver, CO. Abstract 74.
5. Lafeuillade A, Solas C, Halfon P, et al. Differences in the Detection of Three HIV-1 Protease Inhibitors in Non-Blood Compartments: Clinical Correlations. HIV Clin Trials 2002; 3:27-35.
6. Kiser J, Carten M, Wolfe P, et al. Effect of Lopinavir/Ritonavir on the Renal Clearance of Tenofovir in HIV-infected Patients. In Program and Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. Feb 5-8, 2006, Denver, CO. Abstract 570.
7. Gerber JG, Rosenkranz S, Segal Y, et al. Effect of Ritonavir/Saquinavir on Stereoselective Pharmacokinetics of Methadone: Results of AIDS Clinical Trials Group (ACTG) 401. JAIDS 2001; 27:153-160.
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