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  5th International Workshop on Clinical Pharmacology of HIV Therapy
Rome, Italy
April 1-3, 2004		 Back grey_arrow_rt.gif
 
 
 
5th International Workshop on Clinical Pharmacology of HIV Therapy
 
 
  April 1-3, 2004
Rome, Italy
 
Special Report Written for NATAP by Jennifer King, Pharm.D.
The University of Alabama at Birmingham
Division of Clinical Pharmacology
 
CONTENTS
-- It may be helpful to develop combining use of PK & resistance testing
-- Pharmacologic contents of generic HIV drugs used in developing countries
-- Integrating PK (TDM) and resistance testing in evaluating treatment
-- Do tenofovir & abacavir interact intracellualrly?
-- PK in special groups: HCV/HIV coinfection; pregnancy
-- Ritonavir boosting of a double PI regimen
-- Once daily dosing io RTV
-- TMC114 and food
-- Pharmacology of the Pfizer CCR5 receptor UK-427,857
-- Kaletra & NFV resistance: why viral load can be detectable in the absence of PI resistance by estimating the time that LPV and NFV concentrations are in a zone of high selective pressure (HSP) for mutants
-- Can TDM have clinically utility in special settings: pregnancy, liver disease, toxicities
-- TDF 300 mg/emtricitabine (FTC) 200 mg tablet for once daily administration: bioequivalence data
-- SQV pharmacokinetics when administered as a soft gel capsule with RTV versus a hard gel capsule with RTV
-- Nephrolithiasis and IDV/r in coinfected patients
-- Tenofovir and renal effects
-- Combining pharmacokinetic and resistance data to optimize antiretroviral therapy: APV IQ & virologic response
-- We're not ready yet to evaluate intracellular PI activity and levels
-- Distribution of drugs into sanctuary sites such as the CNS and genital tract
 
The 5th International Workshop on Clinical Pharmacology of HIV Therapy was held April 1-3, 2004 at the Universita Cattolica del Sacro Cuore in Rome, Italy. This meeting continues to gain recognition for its impact on the clinical pharmacology of HIV therapy as evidenced by the number of abstracts presented increasing from 53 in 2002 to 82 at this year's meeting. Furthermore, the small number of delegates attending this meeting (approximately 200) made it an excellent forum for open discussions of presented data. Thirty one abstracts were presented orally and 51 in poster format. Many sessions commenced with invited lectures on topics such as: microHAART, Gender/ethnicity issues in pharmacology, intracellular interactions of nucleosides, pharmacological considerations in HIV/hepatitis coinfection and pharmacology of entry inhibitors. All lectures provided a comprehensive overview of current data. The following review of the workshop will briefly discuss selected data most relevant to clinical practice.
 
Session 1: Pharmacological considerations in developing countries
 
Both abstracts presented in this session were conducted in developing countries. S. Schneider and colleagues [ ] reported on generic formulations of zidovudine (ZDV), nevirapine (NVP), lamivudine (3TC), and stavudine (d4T) provided by the ESTHER program for patients in Rwanda. The average drug content/label claim was 99% and in accordance with manufacturers' claims. The authors concluded that good quality generic drugs are available to patients in Rwanda. G. Peytavin and colleagues [ ] evaluated the impact of therapeutic drug monitoring (TDM) of lopinavir/ritonavir (LPV/RTV) on virological responses in protease inhibitor (PI) experienced Caribbean HIV infected patients. Plasma samples were obtained from 74 patients 12 hours after the last dose (known as the minimum plasma concentration or Cmin) of LPV/RTV 400/100 mg twice daily. Dosing was subsequently adjusted to obtain plasma concentrations between 3,000 and 7,000 ng/mL. Twenty-one dose adjustments were performed: 7 decreases in LPV/r dosing to 266/66 mg bid, 8 increases to 533/133 mg bid, 2 additions of RTV 100 mg bid and 4 counseling for non-adherence. After TDM, 85% of patients had LPV Cmin above 3000 ng/mL compared with 68% before TDM. The authors also calculated each patient's Genotypic Inhibitory Quotient (GIQ) to determine whether or not it predicts virological response. Virological response in this study was defined as a minimum viral load (or plasma HIV RNA) of <50 copies/mL at month 6 (M6). The GIQ was calculated as the patients' LPV Cmin divided by the number of protease mutations (determined from a genotypic report). For example, if a patient has a LPV Cmin of 4,000 ng/mL and has 4 PI mutations then his or her GIQ would be 1,000. As the number of mutations increases, the GIQ would decrease suggesting a decreased chance of virological response. In this study, a median GIQ >2133 was associated with a relative risk of 2.43 to reach a plasma HIV RNA below 50 copies/mL. Fifty eight percent of patients were responders and 42% were non responders; mean GIQ was significantly higher in responders vs. non responders (4330 vs. 1780, p<0.001). The GIQ was a better predictor of virological response at M6 compared to a genotypic report or Cmin alone. This was the first of several abstracts presented at this meeting which supports integrating pharmacokinetics and resistance testing to predict clinical outcome.
 
Session 2: Clinical Pharmacology of nucleoside analogs
  • tenofovir and abacavir—is there an interaction?

 
Early virologic failure has been noted with regimens containing 3 nucleoside reverse transcriptase inhibitors (NRTI). For example, JE Gallant, et al [ ] recently reported that 49% of patients receiving tenofovir (TDF), abacavir (ABC) and 3TC did not respond to therapy compared with 5% receiving efavrienz (EFV), ABC and 3TC. One theory behind this failure is a potential pharmacological interaction between TDF and ABC on an intracellular level. We know that most nucleoside analogs have to first enter cells and then once inside, they are phosphorylated to the triphosphate form which is active against HIV. Co-administration of two or more drugs that are phosphorylated intracellularly may potentially reduce the drugs' activity. Therefore, A. Fridland and colleagues [ ] examined whether TDF and ABC interact intracellularly thus reducing their activation. To answer this question, the authors conducted an in vitro study (meaning outside the body or in an artificial environment) where human cells were incubated with ABC in the presence and absence of TDF and with TDF in the presence and absence of ABC; phosphorylation of both drugs occurred in all cells. Neither ABC nor TDF was found to affect each others phosphorylation. Results from this study were supported by another abstract from T Hawkins and colleagues [ ] who conducted a similar study examining ABC and TDF in vivo (meaning in the body). Cells were collected from 15 HIV-infected patients receiving TDF, ABC and a third NRTI. Median intracellular concentrations of the phosphorylated forms of ABC and TDF were similar at baseline (141 and 87.2 fmol/106 cells, respectively) compared with day 28 (120 and 89.6 fmol/106 cells, respectively). The authors concluded that these data in patients indicate no intracellular interaction between TDF and ABC. In summary, these two studies present important findings in clinical pharmacology; virological failures seen with 3 NRTI regimens are unlikely due to intracellular drug interactions. As a result of these conclusions, other potential mechanisms for reduced activity should be explored.
 
Session 3: Pharmacokinetics of special populations
 
Liver function changes in patients co-infected with HIV and hepatitis C (HCV) may affect antiretroviral pharmacokinetics. Two abstracts evaluated NVP and nelfinavir (NFV) pharmacokinetics in HIV/HCV co-infected patients. T. Lavrut, et al [ ] described NVP pharmacokinetics in 10 HIV+ HCV- patients compared with 10 HIV+HCV+ patients. Both groups were comparable in age (median = 40.5 years), weight (median = 68.5 kg) and duration of NVP therapy (median = 38.5 months). However, AST (0.74 vs. 1.32 ULN, respectively) and ALT (0.84 vs. 1.51 ULN, respectively) were significantly lower in HCV- vs. HCV+ patients (p<0.05). NVP Ctrough (3.39 vs. 3.44 mg/L), Cmax (5.27 vs. 5.36 mg/L), AUC (51.72 vs. 51.95 mgxh/L) and t1/2 (12.3 vs. 14.0 h) did not differ in HCV- vs. HCV+ patients. The similarity in NVP pharmacokinetics between the 2 groups supports the use of typical NVP dosing in co-infected patients with mild chronic hepatitis. (note from Jules Levin: NVP can infrequently be associated with risk for serious hepatotoxicity; women, and women with CD4s>250, and men with CD4s>400 high CD4s are at higher risk for hepatic events; increased AST or ALT levels and/or co-infection with hepatitis B or C at the start of antiretroviral therapy are associated with a greater risk of hepatic adverse events. You can read the FDA statements in this at: ).
 
In contrast, reduced doses of NFV in patients co-infected with HIV and HCV appear to provide concentrations within the target range and do not compromise viral control. R. Maserati and colleagues [ ] evaluated NFV pharmacokinetics in 20 HIV/HCV co-infected patients with cirrhosis. Two groups were evaluated: patients in group 1 started on full dosage NFV (1250 mg twice daily or 750 mg three times daily) and patients in group 2 started on a lower dosage (<1200 mg twice daily). Once the AUC was available, TDM was performed to attain an AUC in the range of 45,000 to 75,000 ng/mL ± 30%. Group 1 included 12 patients, 8 of whom required dose reduction. One patient decreased to 250 mg twice daily, 4 patients to 500 mg twice daily, 1 to 750 mg twice daily and 2 patients to 1000 mg twice daily. Median AUCs before and after reduction were 149,500 and 87,000 ng/mL, respectively. Group 2 included 8 subjects, none of whom required dose reduction. Virologic suppression (defined as plasma HIV RNA <50 copies/mL) was reached/maintained in 14 cases. These data are not surprising since earlier data from the same authors showed increased NFV plasma levels in HIV/HCV co-infected patients compared with HIV infected patients after receiving multiple doses of NFV 1250 mg twice daily [ ]. (note from Jules Levin: I think these questions about dosing for all ART HIV drugs in coinfected patients need clear characterization by well designed studies examining different stages of liver disease from no fibrosis through cirrhosis. Although increased drug levels may result in patients with hampered liver function & hepatitis we have little data on the clinical significance of this. A little research shows that if ALT increase above 4-5 times above the upper limit of normal (200-250) liver disease progression may be affected).
 
The third abstract of interest in this session was presented by R van Heeswijk [ ] and colleagues on the pharmacokinetics of NFV 1250 mg twice daily and it active metabolite M8 during and after pregnancy. NFV and M8 pharmacokinetics were assessed in 11 women during the 3rd trimester of pregnancy (TT) and post partum (PP). Median NFV AUC12 and C12h were 25.2 mgxh/L and 0.54 mg/L during TT compared with 33.5 and 1.4 mg/L PP, respectively. Median M8 AUC12 and C12h were 2.8 mgxh/L and 0.06 mg/L during TT compared with 9.43 and 0.18 mg/L PP, respectively. Data showed decreased exposure to NFV during late pregnancy, which reached statistical significance for C12h (p=0.04) and decreased M8 exposure by approximately 70% during pregnancy. These results were similar to those recently reported by Y Bryson and colleagues [ ] which showed a significantly higher NFV AUC PP compared with gestation (36.5 vs. 28.5 mgxh/L, p=0.001) after NFV 1250 mg twice daily. Taken together, these data suggest that TDM may be a useful tool for optimizing NFV dosing in HIV-infected pregnant women.
 
Session 4: Drug-drug interactions
  • Once daily ritonavir in boosting twice daily PI regimen

 
The recent increase in RTV pricing has led clinicians to search for new ways to increase or boost the pharmacokinetics of PIs. One potential mechanism consists of twice daily dosing of a PI with once daily dosing of RTV. This dosing method was examined by A. Luber and colleagues [ ] who determined the pharmacokinetics of SQV administered twice daily with a single dose of RTV. Six HIV-infected patients received SQV hard gel capsules (SQV-hgc) 1600 mg twice daily with RTV 100 mg twice daily for 14 days followed by an intensive pharmacokinetic analysis on day 14. On day 15, subjects received SQV/RTV 1600/100 mg at hour 0 and then SQV 1600 mg with no RTV at hour 12; 12-14 hour pharmacokinetic profiles for both drugs were subsequently performed. SQV AUC12 on days 14 and 15 were 18.13 and 23.24 mgxh/L, respectively. RTV AUC12 on days 14 and 15 were 6.63 and 2.10 mgxh/L, respectively. The authors concluded that SQV exposures were maintained 12-24 hours after RTV dosing despite lower RTV levels. Although this dosing scheme appears promising, larger studies are necessary to confirm the results from this pilot study.
 
M. Boffito and colleagues [ ] also examined the pharmacokinetics of SQV-hgc/RTV in HIV-infected patients; however, in patients concomitantly receiving atazanavir (ATV) or fosamprenavir (FPV). It should be noted that FPV is a pro-drug and once inside the body, it is converted to amprenavir (APV). In the first study, 18 patients received ATV/SQV/RTV 300/1600/100 mg once daily. The addition of ATV to SQV/RTV significantly increased SQV Ctrough, AUC24 and t1/2 by 112, 60 and 17%, respectively and increased RTV Cmax and AUC12 by 34% and 41%, respectively. ATV pharmacokinetics were comparable to those obtained previously in patients receiving ATV/RTV without SQV. In the second study, 18 patients received FPV/SQV 700/1000 mg with RTV 100 or 200 mg twice daily. FPV produced a small reduction in SQV concentrations but was compensated by increasing the RTV dose from 100 to 200 mg. APV levels were not influenced by SQV. Boosting of SQV-hgc by 2 PIs was also examined by R. Bertz and colleagues [ ]. HIV-infected adults in arm 1 received LPV/RTV 400/100 mg twice daily with SQV-hgc 800 mg twice daily. Subjects in arm 2 received LPV/RTV 400/100 mg twice daily and a dose escalation of SQV-hgc as follows: 400 mg twice daily at week 1, 600 mg twice daily at week 2, 800 mg twice daily at week 3 and discontinue SQV-hgc at week 4. SQV pharmacokinetics (when administered with LPV/rtv 400/100) were similar with a 600 mg dose compared with an 800 mg SQV-hgc dose. However, SQV AUC and Cmin were 55% lower after a 400 mg dose compared with 800 mg. In both arms, co-administration of SQV with LPV/RTV did not affect LPV pharmacokinetics. This study suggests that SQV-hgc doses as low as 600 mg twice daily can be co-administered with LPV/RTV 400/100 mg twice daily to HIV-infected adults.
 
Several drug-drug interactions have been noted with TDF and other antiretrovirals, including PIs. K. Scarsi and colleagues [ ] examined the TDF interaction with LPV/RTV by evaluating LPV Cmin in 21 HIV-infected patients. Mean LPV C12h in 14 patients concomitantly receiving TDF was 5.6 mg/L compared with 7 mg/L in 15 patients not receiving TDF. These data suggest no interaction between TDF and LPV/RTV which is in agreement with pharmacokinetic data presented in TDF's package insert. However, intensive pharmacokinetic evaluations after an observed dose in patients receiving LPV/RTV ± TDF is necessary to properly describe this lack of interaction. M. Boffito and colleagues [ ] also examined the potential of a drug-drug interaction between TDF and a PI; however, only TDF pharmacokinetics were reported. Eighteen HIV-infected adults received SQV-hgc/RTV 1000/100 mg twice daily plus TDF 300 mg once daily. No significant change in any TDF exposure parameter was observed over 13 days of therapy. Although these data support co-administration of SQV/RTV with TDF, SQV PK data from these patients is warranted since TDF has been shown to decrease RTV concentrations. The third TDF drug interaction abstract [ ] examined TDF and rifampin (RIF) in healthy volunteers. RIF is commonly used to treat tuberculosis and has been shown to interact with several HIV drugs. Twenty three patients received TDF 300 mg once daily for 10 days followed by the addition of RIF 600 mg once daily for 10 days. Relevant changes in neither RIF nor TDF pharmacokinetics occurred, suggesting no need for dose adjustments of either drug when co-administered.
 
Two abstracts examined the potential drug-drug interaction between ATV and an additional PI. M Guffanti and colleagues [ ] examined ATV pharmacokinetics alone and combined with APV or APV + TDF. An intensive pharmacokinetic evaluation was performed on 9 patients receiving ATV 400 mg once daily, TDF once daily and APV 600 mg twice daily or 1200 mg once daily. ATV Ctrough was 0.073 mg/L in patients receiving ATV/APV/TDF compared with 0.110 mg/L in patients receiving ATV +TDF and 0.251 mg/L in those receiving ATV alone. The authors concluded that plasma ATV concentrations seem to be lower in regimens containing APV and TDF compared with ATV/TDF or ATV alone. However, APV dosing in this study was 600 mg twice daily or 1200 mg once daily. In order to truly elucidate this drug-drug interaction, a larger study in which all patients receive the same APV dose at the same time interval needs to be performed. A second study examined ATV pharmacokinetics with and without SQV-hgc [ ]. Twenty-one HIV infected adults received ATV 400 mg once daily ± SQV-hgc 1200 mg once daily. Plasma samples were obtained at time 0 (after an observed dose and used as the Ctrough) and 2, 3 and 12 hours after the dose. No statistical differences were found in any ATV pharmacokinetic parameter between those patients receiving and not receiving SQV. ATV Ctrough was below the wildtype IC90 (drug concentration required to inhibit 90% of virus replication) of 14 ng/mL in 4/7 patients receiving ATV/SQV and 2/14 receiving ATV alone. Furthermore, 6/7 patients receiving SQV had a Ctrough below the SQV minimum effective concentration (MEC) of 100 ng/mL. The authors concluded that SQV-hgc 1200 mg once daily co-administered with unboosted ATV cannot be recommended in the clinic setting; yet, the addition of RTV boosting could overcome this suboptimal therapy. This conclusion from such a small dataset may not be appropriate. A formal pharmacokinetic study evaluating the optimal dose for combining ATV and SQV-hgc should be performed.
 
Session 5: Pharmacology and pharmacokinetics of new drugs
 
Several posters examined the pharmacokinetics of tipranavir (TPV)/RTV alone and co-administered with other medications. The first abstract examined the effect of TPV/RTV 500/200 mg twice daily on the pharmacokinetics of fluconazole 100 mg in healthy volunteers [ ]. Fluconzaole plasma concentrations were not affected by TPV/RTV. However, TPV C12h increased 104% in the presence of fluconazole (59.5 vs. 29.1µM/L). The clinical relevance of this interaction is unclear and should be further explored. Another pharmacokinetic evaluation of TPV in 23 healthy volunteers examined the interaction with the antacid, magnesium/aluminum hydroxide (Maalox) and the lipid-lowering agent, atorvastatin (Lipitor) [ ]. TPV/RTV increased the atorvastatin AUC approximately 9 fold and inhibited formation of it active metabolites. A single dose of atorvastatin 10 mg had no effect on the pharmacokinetics of TPV. Simultaneous ingestion of Maalox and TPV/RTV decreased TVP AUC12, Cmax and C12h approximately 28%. The authors concluded that patients receiving TPV and atorvastatin should be closely monitored. Furthermore, administration of an antacid such as Maalox should occur 1 hour before or 2 hours after the administration of TPV. Very interesting pharmacokinetic data on TPV/RTV combined with SQV, APV or LPV were also reported [ ]. HIV-infected patients (n=296) received LPV/RTV 400/100 mg, APV/RTV 600/100 mg, SQV/RTV 1000/100 mg or TPV/RTV 500/200 mg, all twice daily. After 2 weeks of therapy, TPV/RTV 500/100 mg was added to the first 3 dosing regimens. Cmin, Cmax and AUC of APV, LPV or SQV were significantly decreased when TPV/RTV was added to the regimen. TPV Cmin did not appear to differ significantly between the treatment arms. Additional studies are necessary to define the magnitude of these drug interactions and their appropriate doses.
 
The pharmacokinetics of TMC114, a novel PI and RTV were reported at this meeting a year ago. R. Hoetelmans and colleagues [ ] followed up with a description of the effect of food on the tablet and solution formulation of TMC 114. A single 400 mg dose of the oral solution and tablet were administered with RTV 100 mg to 15 healthy volunteers under fasted and fed conditions. Intake of food with the tablet formulation increased the amount of drug in the body or AUC approximately 42%. No differences in systemic exposure were noted for the oral solution between the fasted and fed states. The authors concluded that the tablet formulation of TMC 114 should be administered with food.
 
Activity of the oral CXCR4 antagonist AMD070 at escalating doses of 50 to 400 mg were described by N Stone and colleagues [ ]. The drug was well absorbed reaching peak plasma concentrations 0.5 to 4 hours post dose and changes in Cmax and AUC were dose proportional. Plasma concentrations 12 hours after a 400 mg dose stayed above the concentration required to be 90% effective (EC90) for most subjects.
 
Several abstracts were presented on the pharmacology of the CCR5 receptor UK-427,857 in healthy volunteers. The first examined the effect of UK-427,857 on the cytochrome P450 substrate midazolam [ ] and the second examined the effect of the CYP3A4 inhibitor, ketoconazole and SQV on UK-427,857 pharmacokinetics [ ]. It should be noted that many antiretrovirals are substrates for the CYP450 enzyme system. In other words, once the drug reaches the liver, cytochrome P450 enzymes metabolize (or break down) the drug. If the substrate (or drug) is administered at the same time as another drug that is an inhibitor (which decreases the activity of the enzymes) or an inducer (which increases the activity of the enzymes) then the plasma concentrations of the substrate will either increase or decrease. UK-427,857 300 mg administered twice daily slightly increased midazolam AUC and Cmax by 20%. No significant effect was seen on midazolam t1/2. Taken together, these data suggest that UK-427,857 neither increases nor decreases the activity of CYP3A4 enzymes. Ketoconazole and SQV both increased UK-427,857 Cmax to a similar degree. Ketoconaozle caused a slightly greater increase in AUC compared with SQV. These data suggest that drugs which partly inhibit CYP3A4 enzymes (such as RTV) will increase the systemic exposure of UK-427,857. Additional studies of these interactions are warranted.
 
Session 6: Therapeutic drug monitoring: LPV/r & NFV resistance
 
R. Bertz and colleagues [ ] proposed a very interesting theory which may help explain the large differences in viral resistance observed between LPV/RTV and NFV regimens. Previous data indicate that LPV/RTV based therapy produced significantly less PI resistance compared with a NFV based therapy (0 vs. 45%). However, viral load was detectable in some patients without the presence of LPV resistance. The goal of this study was to explain why viral load can be detectable in the absence of PI resistance by estimating the time that LPV and NFV concentrations are in a zone of high selective pressure (HSP) for mutants. In other words, if drug is absent when virus replication occurs, then selective pressure (the ability for mutants or changes in the virus to develop) is low. If virus replication occurs frequently and in the presence of drug, then selective pressure is high. The authors theorized that the selective pressure is highest at drug concentrations between the IC50 for an initial single mutant HIV and wild-type HIV. The HSP zone was estimated as 0.06 to 0.2 µg/mL for LPV and 0.5 to 2.5 µg/mL for NFV. Using pharmacokinetic parameters of each drug obtained from HIV-infected subjects, the authors determined that after a 400/100 mg dose of LPV/RTV the median time to reach the HSP zone was 24.6 h and the time in the HSP zone was 3.8 h. The time for NFV to reach the HSP zone after a dose of 1250 mg was 4.9 h and the time in the HSP zone was 7.5 h. The authors concluded that NFV concentrations rapidly entered the HSP zone and remained longer inside the zone compared with LPV/RTV. Furthermore, the incidence of resistance may be a combination of adherence patterns, size of the HSP zone, time to the beginning of the HSP zone, time that drug concentrations are in the zone and time the drug concentrations are below the HSP zone. This very interesting theory should be further tested with other antiretrovirals.
 
Staszewik and colleagues [ ] evaluated pharmacokinetics of responders and non responders receiving a regimen of LPV/RTV plus SQV without any additional antiretroviral therapy. Responders were defined as having a plasma HIV RNA <= 400 copies/mL if baseline plasma HIV RNA was < 100,000 copies/mL or having a plasma HIV RNA <10,000 copies/mL if baseline HIV RNA was >= 100,000 copies/mL. Overall, nonresponders (n=20) demonstrated lower plasma levels than responders (n=36) for all 3 drugs. SQV AUC and Cmin were significantly lower in nonresponders (12,199 ngxh/mL and 287 ng/mL) compared with responders (19,411 ngxh/mL and 562 ng/mL). RTV and LPV Cmin levels were also lower in nonresponders (60 and 2570 ng/mL) compared with responders (129 and 3605 ng/mL). The authors concluded that plasma levels have an impact on virological outcome.
 
Slish and colleagues [ ] evaluated the clinical application of TDM alone and combined with phenotypic resistance testing of antiretrovirals. Phenotypic resistance testing provides each patient's IC50 (or the concentration of drug required to inhibit viral replication by 50%). Forty two plasma trough concentrations (Cmin) from 33 visits were collected from a web based program over 14 months. Twenty-two concentrations were within the expected concentration range, 15 were below and 5 above. The most common factors contributing to unexpected trough concentrations were drug interactions and non-adherence. Dose adjustments were performed in 8 patient visits. Phenotypes, which were available for 13 samples, were used to calculate the IQ (Cmin/IC50) which ranged from 0.1-9.8. The authors concluded that combining TDM and resistance testing provides additional information to rule out malabsorption and/or resistance that leads to virologic failure.
 
Session 7: Pharmacokinetics of existing drugs in new applications
 
B. Kearney and colleagues [ ] presented bioequivalence data on the combination TDF 300 mg/emtricitabine (FTC) 200 mg tablet for once daily administration. Thirty nine healthy volunteers completed the study. TDF and FTC pharmacokinetic parameters after administration of the fixed dose combination were comparable with parameters after administration of the individual dosage forms. Administration of the fixed dose combination was well tolerated with only 18% of patients experiencing an adverse event. M. Harris and colleagues [ ] compared SQV pharmacokinetics when administered as a soft gel capsule with RTV versus a hard gel capsule with RTV. Ten patients receiving various doses of SQV-sgc plus RTV were switched to SQV-hgc plus RTV in the same doses. Total SQV exposure and trough levels did not change significantly when SQV-sgc was replaced with hgc in a RTV boosted regimen.
 
Session 9: Relationship between pharmacokinetics and toxicity
 
The abstract presented by M. Hillebrand and colleagues [ ] in this session is interesting because it resembles a case report rather than a clinical study. However, its description of a patient who developed renal insufficiency while taking TDF with increasing doses of LPV/RTV is worth mentioning. The authors described a 54 year old HIV-infected male who switched to a regimen of d4T, TDF, ABC, EFV and APV after ddI-related pancreatitis. Approximately a year after the switch, 4 LPV/RTV capsules twice daily were added due to virologic failure and a dose increase to 5 capsules pursued a few months later due to inadequate drug levels. Six months after the addition of LPV/RTV, the patient was admitted for abdominal pain and dyspnea; 2 weeks prior, d4T had been replaced by 3TC. Lab results showed renal insufficiency and metabolic acidosis. All antiretroviral therapy was stopped and his creatinine (which measures the kidneys' ability to work) decreased (477 to 129 µmol/L). The patient was rechallenged with the same regimen (except 3TC was excluded) and his creatinine increased. TDF was subsequently discontinued and the patient's creatinine normalized. This report suggests the potential for TDF induced renal insufficiency in the presence of LPV/RTV and warrants continuous monitoring of renal function during its use.
 
G Dragovic and colleagues [ ] examined the risk of nephrolithiasis in HIV infected patients co-infected with HCV and receiving IDV/RTV 400/100 mg twice daily. Twenty two patients were HIV+/HCV- and 27 were HIV+/HCV+. Average follow-up was 4.6 years and nephrolithiasis developed in 11 patients, 4 in HIV+/HCV- group and 7 in the HIV+/HCV+ group. The authors report that administering IDV/RTV to HIV patients co-infected with HCV increases the risk for nephrolithiasis by 3.8 fold.
 
Session 10: Relationship between pharmacokinetics and drug resistance and/or efficacy
 
Although low plasma concentrations of some PIs have been shown to predict virological response in some patients, this pharmacodynamic effect has not been seen with RTV boosted SQV. J. Ananworanich and colleagues [ ] further examined the correlation between SQV Cmin and plasma HIV RNA reduction in HIV-infected patients receiving SQV-hgc/RTV 1600/100 mg once daily. Decreases in plasma HIV RNA did not correlate with SQV Cmin 8 weeks after therapy. Low SQV Cmin was defined as < 0.05 mg/L (for wildtype) and <0.1 mg/L (threshold for changing SQV dosing). The likelihood of having low SQV Cmin was similar in patients with and without virological success. The authors concluded that plasma SQV Cmin did not correlate with HIV RNA response in these patients and suggested that measuring PI levels in the intracellular compartment rather than in plasma may be more accurate. Before this can occur, however, the methodology used to measure intracellular PIs needs to undergo rigorous quality assurance and proficiency testing and it relevance to the clinic needs to be established.
 
A. Barrail and colleagues [ ] examined the correlation between various methods of calculating APV IQ and virological response. IQu was defined as the Cmin/IC90; IQhs was defined as the Cmin /IQhs (IC90 in additional human serum); and IQgen was defined as the Cmin/number of protease resistance mutations (an early study referred to this as the GIQ). The authors concluded that among patients with PI resistance, the IC90, number of protease mutations and the IQgen were the best predictors of virological response to APV/r. Cmin values did not predict virological response but may have been a result of high APV Cmin value obtained in these patients. This study also supports the use of combining pharmacokinetic and resistance data to optimize antiretroviral therapy.
 
Session 11: Drug distribution to sanctuary sites
 
Distribution of drugs into sanctuary sites such as the CNS and genital tract depend upon factors including extent of protein binding and the role of drug transporters. For example, if a drug is highly bound to proteins in the blood (or plasma) then less "free" drug is available. Only free drug can cross membranes and be effective. J. King and colleagues [ ] described the protein binding characteristics of IDV when given in combination with RTV. Mean IDV protein binding was similar in patients receiving IDV/RTV 800/200 mg once daily compared with 400/400 mg once daily (53.4% vs. 51.8%); both were less than previously published data with IDV alone (~61%). Furthermore, the amount of drug bound to proteins 12 hours after the dose was much higher than 3 hours after the dose, when the total amount of IDV in the plasma was highest (Cmax). In other words, more "free" drug was available to cross membranes 3 hours after the dose compared with 12 hours after the dose. The authors concluded RTV appears to affect IDV protein binding characteristics and IDV protein binding may be higher at lower total plasma concentrations. Another study conducted by R. Garraffo and colleagues [ ] evaluated intracellular concentrations of IDV in patients also receiving 2 different dosages of IDV/RTV. Peripheral blood mononuclear cells (PBMCs) were examined from HIV-infected patients receiving IDV/RTV 400/100 (n=8) or 800/100 mg (n=9) twice daily. The ratio of intracellular concentration (amount of drug in the cell) to plasma concentration was higher with the 800/100 mg group for trough (7.45 vs. 4.87) but not at the peak (6.26 vs. 6.78). The authors concluded that IDV/RTV regimens provide adequate intracellular concentration yet the 800/100 dose appears to better maintain high trough levels at the site of viral replication.
 
Concluding Remarks
 
Very interesting data were presented at this year's International Workshop on Clinical Pharmacology of HIV Therapy. Some of these data will not immediately affect clinical practice. However, the clinical impact will eventually be noted as these ideas are expanded and researched further. For example, we learned from several abstracts the advantage of combining pharmacokinetics and resistance testing. The next step in this area of research is devising a tool which combines these two methods and helps guide clinicians in choosing appropriate antiretroviral therapy. We also learned that failure of antiretroviral regimens containing TDF, ABC and an additional NRTI is not a result of an intracellular interaction, which was originally hypothesized by many. Other mechanisms for this failure should be evaluated. Abstracts on TDM of antiretrovirals continue to be highly represented at this meeting. Although many of these studies show interesting results, the most appropriate place for TDM in clinical practice seems to be in those patients with extenuating circumstances including but not limited to pregnancy, cirrhosis, and potential antiretroviral toxicities.
 
References
 
  1. Schneider S, Schuman M, Omes C, Malibolo MJ, Demeester R, Karasi JC, Wennig R, and Arendt V. Antiretroviral (ARV) therapy among advanced-stage, indigent patients in the funded ESTHER programme in Kigali, Rwanda [abstract 1].
  2. Cabie A, Lamotte C, Dos Santos G, Abel S, Cesiare R, and Peytavin G. Therapeutic drug monitoring (TDM) of lopinavir/ritonavir (LPV/r) combination in Caribbean HIV infected patients [abstract 2].
  3. JE Gallant and others. Early non-response to tenofovir DF (TDF) + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz (EFV) + ABC and 3TC: ESS30009 uplanned interim analysis. [abstract H-1722a (Latebreaker)]. Abstracts from the 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd ICAAC). September 14-17, 2003. Chicago, IL.
  4. Ray A, Vela JE, Olson L, Eisenberg G and Fridland A. Lack of negative interaction between tenofovir and abacavir in human cells [abstract 5].
  5. Hawkins T, Veikley W, StClaire R, Hey A, Guyer B and Kearney BP. Intracellular pharmacokinetics of tenofovir-DP and carbovir-TP in patients receiving triple nucleoside regimens. [abstract 6].
  6. Lavrut T, Heripret L, Durant J, Serini MA, Carsenti H, Dellamonica P, and Garraffo R. Pharmacokinetics of nevirapine in HIV-HCV coinfected patients [abstract 8].
  7. Maserati R, Zucchi P, Briganti E, Roda R, Sacchelli L, Gatti F, Delle Foglie P, Nardini G, Fabris P, Mori F, Castelli P, Testa L, Villani P, Ravasi G, Cusato M, and Regazzi MB. Nelfinavir (NFV) pharmacokinetics (PK) in HIV-HCV coinfected patients with cirrhosis [abstract 12].
  8. Maserati R, Seminari E, Villani P, Marubbi F, Zucchi P and Regazzi MB. Clincal pharmacokinetics of nelfinavir in HIV-HCV co-infected patients. [abstract 6.2]. In Programs and abstracts of the 3rd International Workshop of Clinical Pharmacology of HIV Therapy. April 11-13, 2002. Washington, DC.
  9. Van Heeswijk R, Khaliq Y, Gallicano K, Bourbeau M, Seguin I, Phillips E, and Cameron B. The steady-state pharmacokinetics (PK) of nelfinavir (NFV) and M8 during pregnancy and postpartum [abstract 9].
  10. Bryson Y, Stek A, Mirochnick M, Mofenson L, Connor J, Watts H, Huang S, Hughes M, Cunningham B, Purdue L, Asfaw Y and Smith E. Pharmacokinetics, antiviral activity and safety of nelfinavir (NFV) with ZDV/3TC in pregnant HIV-infected women and their infants: PACTG 353 Cohort 2. [abstract 795-W]. In programs and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002. Seattle, WA.
  11. Luber A, Anderson D, Stryker R, Hill A, Peloquin C, Boffito M and Ruane P. Can ritonavir (RTV) once daily boost saquinavir (SQV) twice daily? A pilot study [abstract 16].
  12. Boffito M, Back D, Kurowski M, Dickinson L, Kruse G, Hill A, Moyle G, Nelson M, Higgs C, Fletcher C, Gazzard B, and Pozniak A. Pharmacokinetics (PK) of saquinavir hard gel (SQV)/ritonavir (RTV) with atazanavir (ATV) or fosamprenavir (FPV) in HIV+ patients (pts) [abstract 17].
  13. Bertz R, Ashbrenner E, Foit C, Sylte J, Scherck J, Becker S, Cameron W, Daar E, Eron J, Hicks C, Yeh V, King K, Da Silva B, and Chiu YL. Assessment of steady-state pharmacokinetics (PK) of three dosing regimens of saquinavir administered as hard gel capsules (HGC) in combination with lopinavir/ritonavir (LPV/r) to HIV-infected adults [abstract 18].
  14. Scarsi K, Postelnick M and Murphy R. Comparison of lopinavir/r plasma levels with and without tenofovir as part of HAART in HIV-1 infected patients [abstract 26].
  15. Boffito M, D'Avolio A, Di Perri G, Sciandra M, Bonora S, Back D, Hill A, Moyle G, Nelson M, Higgs C, Tomkins J, Gazzard B, and Pozniak A. Repeated pharmacokinetics of tenofovir disoproxil fumarate (TDF) in HIV-infected adults receiving saquinavir (SQV) hard gel/ritonavir (RTV) 1000/100 mg bid [abstract 31].
  16. Droste JAH, Kearney BP, Horssen P, Burger DM. Lack of clinically relevant drug-drug interaction between tenofovir DF and rifampin in healthy volunteers [abstract 23].
  17. Guffanti M, Villani P, Seminari E, Cusato M, Schira G, Danise A, Gianotti N, Lazzarin A, Castagna A, and Regazzi M. Atazanavir (ATV) pharmacokinetics when combined with amprenavir (APV) in highly experienced HIV-positive patients [abstract 22].
  18. Canta F, Marrone R, Gonzalez de Requena D, Sciandra M, D'Avolio A, Bonora S, Veronese L, Caci A, and Di Perri G. Pharmacokinetics of atazanavir (ATV) alone and coadministered with saquinavir hard gel capsules (SQVhgc) once daily [abstract 33].
  19. Van Heeswijk R, Sabo JP, MacGregor TR, Elgadi M, Harris F, Mayers D and McCallister S. The effect of tipranavir/ritonavir 500/200 mg bid (TPV/r) on the pharmacokinetics of fluconazole in healthy volunteers [abstract 20].
  20. Van Heeswijk R, Sabo JP, Cooper C, Cameron W, MacGregor TR, Elgadi M, Harris F, McCallister S, and Mayers D. The pharmacokinetic interaction between tipranavir/ritonavir 500/200 mg bid (TPV/r) and atorvastatin, antacid, and CYP3A4 in healthy adult volunteers [abstract 35].
  21. Leith J, Walmsley S, Katlama C, Arasteh K, Pierone G, Blick G, Lazzarin A, Johnson M, Samuels C, Jones P, Quinson A, Kohlbrenner V, Mayers D, and McCallister S. Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51 [abstract 34].
  22. Hoetelmans R, Lefebvre E, van der Sandt I, Marien K, De Pauw M, Peeters M, van der Geest R, Vanstockem M, and Parys W. Pharmacokinetics and effect of food on TMC 114, a potent next generation protease inhibitor, boosted with low dose ritonavir [abstract 39].
  23. Stone N, Dunaway S, Flexner C, Calandra G, Wiggins I, Conley J, Snyder S, Tierney C, and Hendrix C. Biologic activity of an orally bioavailable CXCR4 antagonist in human subjects [abstract 36].
  24. Abel S, Russell D, Ridgway C, Medhurst C, Whitlock L, Weissgerber G, and Muirhead G. Effect of CCR5 antagonist UK-427,857, on the pharmacokinetics of CYP3A4 substrates in healthy volunteers [abstract 40].
  25. Abel S, Russell D, Ridgway C, Medhurst C, Weissgerber G, and Murihead G. Effect of CYP3A4 inhibitors on the pharmacokinetics of CCR5 antagonist UK-427,857 in healthy volunteers [abstract 41].
  26. Bertz R, Chiu YL, Foit C, Horn P, Selness, Bernstein B, Fath M, and Kempf D. Estimation of selective pressure by lopinavir/ritonavir (LPV/r) vs. nelfinavir (NFV) by examination of terminal-phase pharmacokinetics (PK) at steady state [abstract 44].
  27. Staszewski S, Dauer B, Carlebach A, Mosch M, Gute P, Klauke S, Kurowski M and von Hentig N. The LOPSAQ study: 12-hour pharmacokinetic analysis of HIV+ patients treated with the salvage regimen lopinavir (LPV/r) plus saquinavir (SQV) without any additional antiretroviral (ART) therapy [abstract 47].
  28. Slish J, Catanzaro L, Esch L, Lliguicota F, DiFrancesco R, Maponga C, Hewitt R, Morse G. Clinical application of therapeutic drug monitoring alone and combined with phenotypic resistance testing of antiretrovirals [abstract 59].
  29. Kearney BP, Zong J, Begley J and Shah J. Bioequivalence of combination tenofovir DF/emtricitabine tablets for one-pill once daily administration [abstract 62].
  30. Harris M, Alexander C, Bonner S, Ting L, McNabb K, Harrigan PR and Montaner JSG. Soft gel and hard gel formulations offer similar exposure to saquinavir in ritonavir-boosted regimens [abstract 68].
  31. Hillebrand M, Burger D, and Frissen P. Tenofovir serum levels in an HIV-infected patient with tenofovir related renal insufficiency [abstract 72].
  32. Dragovic G, Jevtovic D. Nephrolithiasis induced with combination indinavir + ritonavir in HIV-infected patients co-infected with hepatitis C virus [abstract 73].
  33. Ananworanich J, Hill A, Siangphoe U, Sankote J, Yakasem S, Burger D, Cooper D, Phanuphak P, Ruxrungtham K, Hirschel B. Short-term HIV RNA reductions independent of saquinavir Cmin-analysis of 72 Thai patients given saquinavir/r with 2 NRTIs [abstract 75].
  34. Barrail A, Droz C, Morand-Joubert L, Dam E, Le Tiec C, Clavel F, Chene G, Raguin G, Girard PM and Taburet AM. Calculation and predictivity of inhibitory quotients of amprenavir in heavily pretreated patients [abstract 77].
  35. King JR, Gerber JG, Fletcher CV, Bushman L, and Acosta EP. Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy [abstract 79].
  36. Garraffo R, Lavrut T, Simonet P and Pugliese P. Intracellular concentration of indinavir (IDV) in patients with AIDS receiving two different dosages of indinavir/ritonavir (IDV/rtv) [abstract 82].