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SUMMARY OF THE 6TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF HIV THERAPY
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Quebec, Canada, April 2005
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
".....The development of new CCR5 HIV drugs (PK described below) that specifically target virus resistant to first line therapies is very encouraging for the future of HIV therapy... the abstracts are available at the website www.hivpresentations.com ......Understanding the clinical pharmacology of drugs that we use in therapeutics is the only way we can optimize therapeutic outcome and minimize toxicity..... For the general population TDM for HIV drugs is not helpful but this does not exclude the utility of TDM in very specific populations where the PK and PD of these drugs are less predictable...."
TOPICS
--Gender
--famotidine effect on atazanavir PK
--Kaletra and lamotrigine pk
--Pk of paroxetine (Paxil) and fosAPV/RTV (700/100 mg b.i.d.)
--Pk of RTV 200 mg b.i.d. and prednisone 20 mg single dose in healthy volunteers
detailed drug-drug interaction between tenofovir and ATV/RTV
-- tenofovir and ATV/RTV
-- TMC114 and omeprazole and ranitidine
-- esomeprazole 20 mg on the PK of APV when administered as fosAPV
(fosamprenavir, LEXIVA) 1400 mg b.i.d. or fosAPV 700mg/RTV 100 mg b.i.d. to steady-state
--nevirapine or EFV concentrations in patients taking rifampin
--pregnancy and plasma concentrations of HIV protease inhibitors, NRTIs, nevirapine & TDM use during pregnancy
--unexpected hepatoxicity of SQV/RTV (1000/100 mg b.i.d.) when used with rifampin
--HCV co-infection and PK of LPV/RTV
--PK in children & infants: nevirapine, RTV, NFV. TDM suggested
-- validated HPLC-MS/MS method for nukes
-- needle-free gas powered injector for subcutaneous administration of enfuvirtide results
-- PK, efficacy, and safety of the combined use of ATV (Reyataz) with Kaletra
--FDA requirements for fixed-dose combinations
--TDM, hepatotoxicity
--microbicides
-- three CCR5 receptor antagonists in advanced stages of development. 873140 is being developed by GlaxoSmithKline, Maraviroc (UK-427857) by Pfizer, and SCH 417690 by Schering-Plough
-- PK data on Tibotec's new PI, TMC 114, and two NNRTIs, TMC 125 and TMC 278
The 6th International Workshop on Clinical Pharmacology of HIV Therapy was held in Quebec City on April 28-30. Even though the weather did not cooperate as it rained during the entire meeting, the presented abstracts were generally of good quality and invited speakers did an excellent job in presenting important information related to HIV pharmacology. In addition to the usual format of oral presentations and poster presentations there were two sessions lead by Drs. Boffito and Anderson that discussed the highlight of the posters. In general this addition to the meeting was well received as posters frequently do not get the attention they deserve.
It is impossible to review all the abstracts from the workshop thus I reviewed selected abstracts that in my opinion have significant implications for the treatment of HIV infection. The meeting was divided into six sessions and I will present the abstracts and my interpretations from those sessions.
Session 1: Pharmacokinetics/Resistance/Inhibitory Quotient
This session started with an invited lecture by Dr. Dan Kuritzkes. The aim of his lecture was to try to demystify the issue as to why certain triple nucleoside RT inhibitor regimens cause early and high rate of virologic failure. The lecture reviewed the data that NRTI resistance develops through essentially two diverse mechanisms. One is by decreased nucleotide analogue incorporation and the other by increased nucleotide analogue removal. Thymidine nucleoside analogue resistance mutations select for increased analogue removal. The first few mutations are somewhat specific for the thymidine analogues but as more mutations accumulate resistance to all nucleoside analogues develop. The 65R, 74V, and 184V mutations decrease the excision process and therefore can resensitize the virus to thymidine analogues. As to why the combination of ABC, tenofovir, and 3TC failed in clinical trials remains unexplained. These are three potent nucleoside/tide analogues that do not share pathways in enzymatic phosphorylation. Four possible explanations were brought forward by Dr. Kuritzkes but no convincing evidence for any of them was provided. 1. Concerted pressure on K65R (but not all subjects failed with this mutation). 2. Pharmacokinetic interaction within cells (no evidence for this so far). 3. Regimen potency (maybe but how can this be possible when individually each drug in monotherapy can reduce HIV-RNA by 1.5 log?). 4. Differential effect of drugs in different cellular compartments (no real evidence for this so far). Thus we are left without a rational explanation for this adverse pharmacodynamic interaction. Possibly the most convincing hypothesis was put forth by Kakuda et al. (AIDS 18:2442, 2004) that somehow tenofovir's inhibition of purine nucleoside phosphorylase (PNP) may be the culprit. PNP inhibition may also explain the CD4 lymphocytopenia associated with the concomitant use of tenofovir and ddI. PNP inhibition is associated with increased concentrations of intracellular dATP and dGTP which could oppose the action of adenosine and guanosine analogues. In addition excess dGTP results in the inhibition of ribonucleotide reductase which could affect DNA synthesis and cause CD4 lymphocytopenia. This hypothesis can be proved or disproved by measuring plasma levels of deoxyguanosine, guanosine, and inosine before and after administration of tenofovir in addition to the accurate quantitation of dATP and dGTP in CD4 lymphocytes.
Session 2: Drug-Drug Interactions
This session had the most number of oral and poster presentations. The session started with the invited lecture Dr. Richard Kim on drug transporters and HIV therapy. Although the lecture was an excellent update on specific transporters that may be important in the activity of some antiretroviral drugs, at this point in time their importance is theoretical because there are no definitive data on how genetic polymorphism of these transporters affects the antiretroviral efficacy of these drugs. Dr. Kim spent some time on the transporter MRP-4 that is involved in the efflux of the monophosphate metabolites of nucleosides. MRP-4 is expressed in lymphocytes and macrophages which would suggest that both MRP-4 expression and MRP-4 activity can determine the nucleoside monophosphate concentration within cells. Over-expression of MRP-4 in vitro has been demonstrated to reduce the activity of zidovudine. MRP-4 variants (single nucleotide polymorphisms, SNP) have been described and interestingly these variants have increased activity suggesting that the existence of these variants may result in decreased nucleoside activity as nucleoside monophosphates would be more avidly exported out of cells. Whether this has any clinical importance during HIV therapy has yet to be demonstrated.
Dr. Kim also spoke about how transporters could modulate the nuclear pregnane X-receptor (PXR) induction by rifampin. It is well known that most of the cytochrome P450 enzyme (CYP) induction occurs through interaction with PXR. He described experiments that demonstrated that rifampin gets into cell lines through the liver specific OATP-C transporter. The level of OATP-C expression in cell lines determined the extent of PXR activation by rifampin. Since OATP-C variants exist with reduced transporter activity, these data would suggest that some of the variability in rifampin's induction of CYPs may be secondary to OATP-C polymorphism. This has yet to be demonstrated in people but this transporter is important in the hepatic clearance of HMG CoA reductase inhibitors, pravastatin and rosuvastatin. OATP-C variants have been associated with increased plasma concentrations of pravastatin (Clin Pharmacol Ther 73:554, 2003).
Abstract 8 by Yeh et al. from the University of North Carolina examined the intestinal and hepatic activity of CYP3A4 in the absence and presence of Kaletra. The investigators measured the oral clearance of midazolam to estimate intestinal/hepatic first pass CYP3A4 effect of Kaletra¨ and systemic clearance of midazolam after intravenous administration to estimate that hepatic CYP3A4 effect of Kaletra. These studies were performed in 14 HIV-seronegative volunteers and Kaletra was administed for 10 days to achieve steady state. Yeh reported that Kaletra reduced oral midazolam clearance by 92% and systemic clearance by 77%. These data are important because it clearly demonstrates that RTV-containing PIs reduce both the first pass and systemic drug metabolism via CYP3A4. Thus drug-drug interaction studies with RTV-containing PIs which demonstrate induction of metabolism is not secondary to RTV's induction of CYP3A4 but induction of other CYP isoforms and/or glucuronidation. For example methadone is thought to be mainly metabolized by CYP3A4 but RTV induces methadone metabolism. The above data suggest that isoforms others than CYP3A4 are involved in methadone's metabolism (Chirality 13:36, 2004).
Abstract 9 by Dickinson et al. from Liverpool retrospectively examined the impact of gender on the pharmacokinetics of SQV and RTV (1000/100 mg b.i.d.) in HIV-infected subjects from four PK studies. Although the overall number of female subjects were limited (n=6), PK differences between the genders were very significant. Both SQV and RTV area-under-the curves (AUCs), Cmax, Cmin were 2-3-fold higher in the female subjects compared to male subjects. In a separate group these investigators also examined P-gp and MRP expression in PBMCs of 93 HIV-infected subjects (30 females) and found that the expression of these transporters was significantly higher in the male subjects. Although overall drug exposure was consistently higher in females, drug half-lives showed no gender differences. These data suggest that most of the PK difference occurs along the first pass-absorption step and not during systemic elimination. Although this is not the first time gender differences in SQV PK have been described in both HIV-infected and seronegative subjects (JID 189:1176, 2004; 12th CROI, abstract 655), the overall clinical significance of these observations have not always been obvious although ACTG 359 did report a better antiretroviral response in female subjects in a PI-salvage setting (JID 189:1176, 2004). Interestingly abstract 50 by Robertson et al. could not demonstrate PK differences with SQV in male and female subjects in this HIV-seronegative study using Fortavase¨ without RTV. In sum these data strongly suggest that the gender differences in SQV PK may be secondary to differences in RTV PK and not SQV proper. Since in clinical practice SQV is always used with RTV, these gender differences may carry pharmacodynamic consequence especially during the treatment of PI-experienced subjects.
Agarwala et al. from BMS presented the long awaited data on the effect of famotidine on atazanavir PK (abstract 11). These investigators presented their ATV PK interaction data with omeprazole at CROI which showed that omeprazole should not be used with ATV because of the large decrease in ATV exposure. However H2 receptor antagonists are less potent inhibitors of gastric acid so it remained unclear whether famotidine 40 mg b.i.d. can be safely used with ATV. This was a beautifully designed study consisting of 108 healthy subjects in two separate studies. The first study concentrated on the effect of famotidine on the PK of ATV 400 mg q.d. while the second study examined the effect of famotidine on the ATV PK when ATV/RTV (300/100 mg) is administered. The results showed that famotidine reduced ATV AUC by 41% for ATV 400 mg when the drugs were co-administered but this effect was mitigated by giving ATV 10 hours after famotidine. ATV/RTV with famotidine gave a much higher ATV exposure than ATV 400 mg alone. Thus if H2 blocker use is necessary, ATV/RTV should always be used. Famotidine reduced ATV exposure by only 18% when ATV/RTV was used and this can be corrected by increasing ATV dose to 400 mg. In this study, gastric pH was monitored in the subjects and it was demonstrated that ATV AUC correlated with the gastric pH in the presence of famotidine. The overall message of the study is that famotidine can be used with ATV/RTV but in PI-experienced subjects that require higher concentrations of ATV increasing ATV to 400 mg may be necessary. ATV without RTV would not be optimal but if it can be given 10 hours after AM famotidine and 2 hours before PM famotidine the drug-drug interaction is mitigated. However patients with severe acid related gastrointestinal problems, like erosive reflux esophagitis, clearly require proton pump inhibitors for optimal therapy.
Van der Lee et al. from the Netherlands presented drug interaction data between Kaletra and lamotrigine (abstract 12). Lamotrigine is an anticonvulsant that is also used in the treatment of peripheral neuropathy. Lamotrigine is metabolized by glucuronidation and RTV is known to induce this pathway. The study was performed in HIV-seronegative volunteers. The results showed that Kaletra reduced lamotrigine AUC by 50% which can be corrected by doubling the lamotrigine dose. These data demonstrate that Kaletra, like other RTV containing regimens, is a potent inducer of glucuronidation.
Burger et al. presented drug-drug interaction data in healthy volunteers between paroxetine (Paxil) and fosAPV/RTV (700/100 mg b.i.d.). Paroxetine is presumably metabolized by CYP2D6 which is not a readily inducible enzyme. RTV at high doses has been shown to inhibit CYP2D6 but at 100 mg b.i.d. this does not occur. APV is an inducer of multiple CYP isoforms as well as a moderate inhibitor of CYP3A4. Since depression is commonly associated with chronic medical illnesses like HIV infection, and treatment of depression is associated with improved adherence to antiretroviral therapy exploring this drug-drug interaction has practical consequence. Surprisingly the investigators found that fosAPV/RTV reduced paroxetine AUC by 55%. There was no ready explanation for this drug-drug interaction since it has been thought that paroxetine utilizes CYP2D6 for metabolism. From these data it is likely that paroxetine uses multiple CYPs for metabolism as demonstrated by the drug's interaction with phenytoin (substrate for CYP2C9 and C19). Nonetheless the message from this presentation is that paroxetine dose may need to be increased when used concomitantly with fosAPV/RTV. It will be important to examine whether this drug-drug interaction also occurs with other RTV-enhanced PI regimens.
Penzak and co-workers studied drug-drug interaction between RTV 200 mg b.i.d. and prednisone 20 mg single dose in healthy volunteers (abstract 14). The investigators found that RTV increased prednisolone (active metabolite) exposure by 37% on day 4 of RTV which decreased to 28% on day 14 of RTV. It is unclear whether such a small increase in prednisolone exposure has any physiologic consequence. What is more concerning are the case reports of adrenal suppression with concomitant use of topical fluticasone and RTV use (HIV Medicine 4:149, 2003; AIDS 13:1803, 1999).
There were numerous poster presentations on drug-drug interactions. I will briefly mention a few with clinical application.
· Abstract 16 described detailed drug-drug interaction between tenofovir and ATV/RTV (300/100 mg) in HIV-seronegative healthy volunteers. Tenofovir reduced ATV exposure by 11% (Cmin by 20%) but increasing ATV dose to 400 mg resulted in a significant overshoot of ATV exposure. More concerning was the effect of ATV on TDF concentrations. ATV/RTV (300/100 mg) increased TDF exposure by 37% (Cmin 29%) but when ATV was increased to 400 mg the increase in TDF exposure was 55% (Cmin 70%). The present recommendation is not to alter ATV dose when used concomitantly with TDF.
· Abstract 17 reported on the drug-drug interaction between the Tibotec PI, TMC114 and omeprazole and ranitidine. TMC114 PK was unchanged with these gastric acid inhibitors. Abstract 24 reported on the impact of esomeprazole 20 mg on the PK of APV when administered as fosAPV (LEXIVA) 1400 mg b.i.d. or fosAPV 700mg/RTV 100 mg b.i.d. to steady-state. All the changes in PK were very minor and generally not significant. Thus it appears that PPIs interact most dramatically with ATV and very little with other PIs.
· Abstract 19 reported from Liverpool TDM service on the factors influencing EFV concentrations in patients taking rifampin. These investigators found that there was very little difference in the PK of EFV whether 600 mg or 800 mg was used with rifampin. However more subjects with a body weight less than 60 kg and EFV dose of 800 mg + rifampin had high EFV concentrations (>4000 ng/mL). Since this was a retrospective snapshot, there were no clinical data on EFV toxicity in this group of subjects. Abstract 28 also reported on EFV and rifampin use for tuberculosis and found that 600 mg of EFV is not associated with subtherapeutic EFV concentrations in a small number of subjects (n=5). Perhaps the most convincing data that 600 mg dose of EFV is adequate when used concomitantly with rifampin was published by Patel et al. (JAIDS 37:1166, 2004) where EFV 600 mg with anti-TB therapy containing rifampin resulted in excellent virologic outcome. In contrast abstract 21 reported from Thailand that nevirapine plasma concentrations in the presence of rifampin were reduced by -50%. No virologic outcome was reported in these patients.
Session 3: Pharmacokinetics Special Group and Toxicity
This session began with an invited lecture by Dr. Edmund Capparelli reviewing the clinical pharmacology of HIV drugs in pregnant women. This was an excellent overview demonstrating that physiologic changes associated with pregnancy can alter the volume of distribution as well as protein binding of HIV drugs. However more concerning are the changes in drug metabolizing enzyme activity during pregnancy. For example both CYP3A4 and 2D6 activities are increased during pregnancy thus plasma concentrations of PIs are consistently reduced. For example lopinavir exposure is reduced as much as 50% during pregnancy. IDV, NFV, SQV, and RTV exposures are also reduced quite significantly. In contrast NVP PK is altered very little during pregnancy. In terms of nucleoside RTI, event though the plasma concentrations are reduced during pregnancy, the actual rate of phosphorylation is increased. Since pregnancy is associated with increased variability in the PK of PIs, it may be important to utilize TDM in these patients to prevent virologic breakthrough and development of drug resistance.
Abstract 35 was presented by M. Schutz on the unexpected hepatoxicity of SQV/RTV (1000/100 mg b.i.d.) when used with rifampin in HIV-seronegative healthy volunteers participating in PK study. A total of 28 subjects participated in a two arm study. In arm 1, SQV/RTV was administered for the first 14 days and then rifampin 600 mg q.d. was added to the regimen. In arm 2, rifampin was given for 14 days and then RTV/SQV was added. Although mild hepatoxicity was observed in some of the subjects in arm 1, it was arm 2 that resulted in shutting down this study prematurely. All 9 subjects with SQV/RTV initiated after rifampin had elevations in LFTs. In some the increase in ALT was as high as 2500 U/L (75-fold increase). In some of the subjects, plasma concentrations of rifampin and desacetyl rifampin were elevated suggesting significant hepatic dysfunction. When the study medications were stopped the LFTs reverted to normal in everybody. These findings resulted in the distribution of "Dear Healthcare Provider" warning against using these drug combinations. In a previous drug-drug interaction study using Kaletra + rifampin an unusually high fraction of the subjects (-30%) developed grade 2 (>2.6 x ULN) and grade 3 (>5.1 x ULN) elevations of LFTs (Antimicrob Agents Chemo 48:1553, 2004), but the level of LFT elevation seen with rifampin pretreatment and SQV/RTV is very concerning. In addition, rifampin when used together with ATV/RTV was liver safe (abstract 657, 12th CROI), but again the subjects were not pretreated with rifampin before the introduction of PIs. Since in most clinical setting OIs are treated before the HIV infection, it would not be unusual to have rifampin already on board before initiating HAART therapy. From these data it will be important to design future drug-drug interaction studies with PIs and rifampin where one arm of the study initiates rifampin first before the PIs.
Molto et al. presented abstract 36 which concluded that HCV co-infection does not affect the PK of LPV/RTV if there is no evidence for hepatic dysfunction.
Final oral presentation was by Capparelli et al. on the population PK of nevirapine in infants and children from large datasets collected through PACTG studies. The study concluded that NVP clearance was relatively constant from ages 1-15 years when normalized to BSA. RTV and NFV only have marginal effects on the PK of NVP. There is large inter-patient variability in the PK of NVP. Nonetheless using a dosing algorithm of 150 mg/mm2 would less likely under-dose older children than the FDA weight based dosing. The potential utility of TDM in this population was also suggested.
Abstract 43 by Kruse et al. examined nucleoside phosphorylation in HIV-infected children using a newly developed, validated HPLC-MS/MS method that can simultaneously quantify all the nucleoside triphosphate metabolites within cells except for ZDV-TP. The importance of the study is that the method appears simple and the data look reasonable and not different from what has been reported in adults.
Session 4: Pharmacokinetics of Existing Drugs
This was the shortest session and had only two oral presentations. The first one by Harris et al. (abstract 48) demonstrating that needle-free gas powered injector for subcutaneous administration of enfuvirtide results in bioequivalence to the needle injected enfuvirtide. However there was less cutaneous reaction and patients preferred this method of administration over the needle injection. A larger study is planned to confirm these preliminary observations.
Jetter and colleagues studied the activity of CYP3A4 in HIV-infected, therapy na•ve subjects before and after initiating a Kaletra-based regimen (abstract 49). CYP3A4 was assessed using oral and intravenous midazolam clearance. These investigators could not demonstrate a relationship between LPV or RTV AUC and CYP3A4 activity. The lack of relationship does not necessarily mean that this relationship does not exist but it may be more complex because a CYP3A4 inhibitor (RTV) is in the mix. In addition the role of P-gp in the absorption of these drugs may also confound the data.
Langmann et al. presented data on the PK, efficacy, and safety of the combined use of ATV with Kaletra (abstract 56). The investigators chose to use this triple PI combination in 28 heavily pretreated patients. NRTIs and NNRTIs were added as necessary to the regimen. The overall Cmin of LPV and ATV were equivalent to what is published with these PIs and RTV alone. The tolerability in this small group of patients was reasonable with mild diarrhea, elevated serum lipids, and serum bilirubin as the most common toxicity. In addition efficacy of this regimen was adequate. What is unclear to me is whether three PIs (one is RTV as a booster) are really more efficacious than just a RTV-boosted PI regimen. It is difficult to be convinced without comparative data especially since all the PIs attack the same target.
Session 5: Therapeutic Drug Monitoring
This session started with the invited lecture by Dr. Kellie Reynolds from the FDA discussing the regulatory issues related to fixed dose combination drugs for the treatment of HIV infection. Dr. Reynolds eloquently described the steps necessary for FDA approval of a fixed dose combination drugs. For example, the fixed-dose preparation has to demonstrate stability, adequate in vitro dissolution, and bioequivalence. If the preparation is a new fixed-dose combination, the drug has to be submitted as a NDA (new drug application), but if there is an approved reference drug then an ANDA (abbreviated new drug application) can be submitted. If there is no food requirement stipulated the bioequivalence study has to be performed in both fasted and fed state. Dr. Reynolds concluded that the FDA wants to have an impact on public health beyond the US borders but wants to approve drugs that are safe, effective, convenient, and economical in addition of the same quality as those provided in the US.
Dr. Saye Khoo from Liverpool, UK described a pilot study, POPIN (Pharmacological Optimization of PIs and NNRTIs), that examined the feasibility of TDM/adherence support study in order to design a more definitive prospective study on the utility of TDM in a practice setting (abstract 59). The study was performed in three sites and the adherence support was performed by trained nurses using questionnaires. Plasma concentrations of drugs were obtained for trough and ± 2 hr post dose, and dosing recommendations were made in the TDM/adherence arm but not in the standard of care (SOC) arm. A total of 122 patients were evaluated for end points of a) failure to achieve VL < 50 copies/mL at 24 weeks b) sustained viral rebound of > 50 copies/mL, and c) treatment-limiting toxicity. Subjects were either in the start/switch group (n=37) where modifications in therapy were implemented during follow-up for virologic failure or severe toxicity or in the suppressed group (n=85). The majority of subjects were using NNRTI-based therapy. There were 63 subjects randomized to the TDM/adherence support group and 59 subjects in the SOC group. Data were analyzed using ITT where non-toxicity/failure switches were censored or considered as failure.
The results of this underpowered study showed no benefit of TDM/adherence support whether the data were analyzed as switch=failure or switch=censored. However the total number of subjects who failed/or had toxicity were low (n=19). One of the problems with this study was that physicians followed dose modification advice only 35% of the time. Using these pilot data that demonstrated in this population that only 30% of patients have excessively high/low plasma concentrations of PIs and NNRTIs, and physicians adhere to dosage modifications only 35% of the time, then if TDM is to reduce failure rate by 50%, a study would need to utilize 1720 patients to achieve 80% power for success. POPIN demonstrated the difficulty in designing a TDM study to affect virologic success and toxicity when the HAART regimens are generally effective (>80% success) and not excessively toxic. For the general population TDM for HIV drugs is not helpful but this does not exclude the utility of TDM in very specific populations where the PK and PD of these drugs are less predictable.
Regazzi et al. (abstract 61) developed a validated, limited sampling strategy to accurately estimate Nelfinavir AUC0-12hr. The investigators utilized data from 99 patients where complete PK data were available with a NFV 1250 mg b.i.d. regimen. Using a step-wise multiple linear regression analysis of the data, it was determined that plasma concentrations at time 0 and 4 hours post-dose provides 92% accuracy in predicting NFV AUC0-12hr. This was prospectively validated in both HIV-infected and HIV/HCV co-infected subjects with and without cirrhosis. Although the data are convincing, there are no conclusive data with NFV that either AUC or Ctrough is associated with drug-defined toxicity, or that the AUC parameter is more accurately correlated with drug efficacy.
Abstract 64 by Soriano et al. described a new assay for plasma lopinavir using a high-throughput immunoassay with a turnaround time of about 10 minutes and a plasma volume of 3 ml. An assay of this sort may be able to make TDM for antiretroviral drugs practical.
Abstract 66 by Seminari et al. demonstrated that APV plasma concentration in subjects on fosAPV/RTV is not elevated with HCV co-infection as long as liver cirrhosis is not present. This is similar to what Molto et al. described for LPV/RTV (abstract 36). Thus it appears that HCV infection itself does not affect the PK of PIs but the actual hepatic injury secondary to chronic infection is responsible for the described PK differences with HCV co-infection.
Session 6: Pharmacokinetics of New Drugs
This final session started with an invited lecture by Dr. Craig Hendrix on Microbicides for HIV Prevention: Developmental Challenges for Clinical Pharmacology. This was an elegant, academic presentation that left me feeling that we are far from having an effective microbicide for the prevention of HIV infection. A microbicide has to be protective, localized at the correct site to prevent transmission, and has to be protective longer than viral presence thus clearance of the drug has to be slower than the virus clearance. Presently there are microbicides that inhibit viral attachment and entry, destroy virus by surfactant action, or inhibit viral polymerases. Dr. Hendrix vividly presented preliminary data on some of the anatomical challenges when using microbicides. Probably the greatest challenge is related to the fact that coitus clearly changes the distribution of microbicides and may leave vaginal or rectal mucosal coverage inadequate. The NIH has allocated increasing amount of money in the support for the development of effective microbicides. After identification of an effective microbicide a clinical trial will be necessary to demonstrate efficacy. The clinical trial will require a close surveillance for overall adherence to this mode of HIV prevention.
The other oral presentations dealt with a large amount of data on the clinical pharmacology of antiretroviral drugs in development. There are presently three CCR5 receptor antagonists in advanced stages of development. 873140 is being developed by GlaxoSmithKline, Maraviroc by Pfizer, and SCH 417690 by Schering-Plough. Thus a better understanding of how to use these drugs and what to expect in terms of drug-drug interaction is important.
Adkison et al. described the pharmacology of 873140 (abstract 77). The drug is an allosteric inhibitor of CCR5, which is a host target, and it has a slow receptor offset. At a dose of 600 mg b.i.d. for 10 days the drug reduced viral load by a median of 1.5 log. The drug demonstrated dose proportional increase in AUC and Cmax. Moderate fat food intake increased drug exposure by 47%. AUC24hr correlated well with antiviral response. In addition time above IC50 also showed a good correlation with response. The plasma t1/2 of the drug is 2.5 Ð 4 hrs but receptor occupancy has a t1/2 of 3-6 days. Maximal receptor occupancy on PBMCs is demonstrated at 200 mg q.d. but maximal antiviral activity is at a dose of 600 mg b.i.d. Thus there was no relationship between receptor occupancy and antiviral effect. This dissociation between receptor occupancy in peripheral PBMCs and antiviral effect may be secondary to the fact that most viral production occurs outside of the blood and this drug's distribution into lymphatics has not been adequately described.
Song et al. described the effect of 8731040 on CYP isoform activity in vivo using the Cooperstown cocktail. This cocktail estimates the effect of drugs on CYP1A2, 2D6, 2C9, 2C19, and 3A4 activity by using the metabolism of prototype drugs for specific CYPs. At steady state 400 mg b.i.d. of 873140 showed a 23% reduction in the oral clearance of midazolam (CYP3A4 activity) without any effect on the other CYP isoforms. Thus 400 mg b.i.d. of 873140 is a weak inhibitor of CYP3A4. The clinical importance of the effect of 873140 on CYP3A4 is yet undefined.
Muirhead et al. presented a huge amount of coherent data on Maravoric (UK-427,857) (abstract 76). The drug is metabolized by CYP3A4, has a terminal t1/2 of 13 hrs, and is a P-gp substrate. Food intake decreases Maravoric exposure by 50% and PK of the drug is similar in males and females, patients and volunteers, and in Caucasians and Asians. Maravoric 100 mg b.i.d. had no effect on ethinyl estradiol and levonorgestrel exposure. At 300 mg b.i.d. the drug had no effect on midazolam, zidovudine and lamivudine PK. Since Maravoric is a CYP3A4 substrate, inhibitors of this CYP isoform have been shown to increase Maravoric exposure 3-5-fold. However unexpectedly, SQV (Fortovase) increased Maravoric exposure 4.3-fold, and SQV/RTV increased Maravoric exposure 8.3-fold. This drug-drug interaction is likely to be secondary to inhibition of transporters rather than CYP3A4. Downward dose adjustment of Maravoric can correct for the increased exposure due to CYP3A4 inhibitors like PIs. Both EFV and rifampin induce Maravoric's metabolism but doubling the usual dose of the drug can correct for this metabolic induction. EFV reduces the inhibitory effect of Kaletra and SQV/RTV on Maravoric metabolism by 50%. Interestingly nevirapine had no effect on Maravoric's exposure when examined in HIV-infected patients.
Sansone et al. presented the PK data for SCH 417690 (abstract 78). This drug, like all the others in this class, is a CYP3A4 substrate and neither induces nor inhibits CYPs. The drug is 84% protein bound and has a terminal t1/2 of >24 hours. No drug-drug interaction occurs with tenofovir or combivir. However RTV does increase SCH 417690 exposure approximately 5-fold, but interestingly this effect occurs at 100 mg q.d. dose and the effect is not greater with increasing doses of RTV up to 400 mg b.i.d. EFV is a potent inducer of SCH 417690 metabolism and EFV partially opposes RTV's effect on SCH 417690's exposure.
After the audience got saturated with CCR5 antagonists, Hoetelmans et al. presented PK data on Tibotec's new PI, TMC 114, and two NNRTIs, TMC 125 and TMC 278. TMC 114 is a PI that is administered with 100 mg of RTV. The drug has a long terminal t1/2 of -15 hours and is 95% protein bound. The dose that is used for phase III trials is TMC 114/RTV (600/100 mg) b.i.d. TMC 114 PK is not affected by either concomitant ranitidine or omeprazole. TMC 125 is highly lipophilic NNRTI that is 99.9% protein bound. Plasma t1/2 is -35 hours. The drug has not PK interaction with ddI. The drug has recently been reformulated into a pill and this new formulation increased the overall exposure by 9-fold which should help with pill burden and improve the convenience of drug administration. TMC 278 is the newest NNRTI. The drug is lipophilic, highly protein bound, and has an elimination t1/2 of -45 hours. The drug-drug interaction potential is limited in that it has not been found to induce or inhibit CYP isoforms. The drug has an oral tablet formulation. Food increases drug exposure by 45% and early drug interaction study showed a small increase (15%) in TMC 278 when co-administered with tenofovir.
The development of these new drugs that specifically target virus resistant to first line therapies is very encouraging for the future of HIV therapy. There were many other abstracts at this meeting that I could not cover. However all the abstracts are available at the website www.hivpresentations.com. This workshop is finally achieving the importance it deserves. Understanding the clinical pharmacology of drugs that we use in therapeutics is the only way we can optimize therapeutic outcome and minimize toxicity. This workshop is aiming to achieve that goal.
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