Important note: Information in this article was accurate in September 2002. The state of the art may have changed since the publication date.
At the XIV International AIDS Conference in Barcelona, there were only six oral presentations and approxi-mately 30 posters on pharmacology and drug interactions. A number of the studies presented had potential relevance to resource poor countries, a theme that resonated throughout the conference.
A Cheaper Alternative to Saquinavir-Soft Gelatin Capsules?
Saquinavir was developed in two successive formulations, “hard gel” capsules (SQVhgc, Invirase) and “soft gel”capsules (SQVsgc, Fortovase). Because the soft gel capsules have three-fold greater bio-availability, this formulation has been favored for the treatment of HIV infected patients. While available pharmacokinetic data support the use of once-daily SQVsgc when boosted with ritonavir (SQVsgc/RTV 1600/100 mg), a direct comparison of the pharmacokinetics of once-daily hard gel capsules with soft gel capsules boosted with ritonavir has not been reported.
To address this issue, a team of investigators from Thailand and Australia (HIV-NAT) examined the effect of ritonavir on the pharmacokinetics of SQVhgc [Ananworanich J, et al. Abstract MoPpB2007]. Fourteen HIV infected subjects taking SQVsgc/RTV (1600/100 mg) once daily plus 2 NRTIs for 48 weeks had SQV pharmacokinetics assessed at steady-state and one week after switching to SQVhgc at the same dose. Subjects were then switched back to SQVsgc and continued on this formulation throughout the study. The authors found that the 24 hour area under the curve [AUC(0-24)] of SQVhgc was significantly greater when compared to SQVsgc. The authors attributed this to the slower absorption of the hard gel formulation, resulting in a greater interaction with ritonavir. Other pharmaco-kinetic parameters (Cmax, Cmin) were equivalent for the two formulations. In the U.S. the hard gel
capsule formulation is more expensive than its counterpart. However, according to the study authors, SQVhgc will be less costly to produce then SQVsgc and will also be available in Thailand at a lower cost. If that is the case, SQVhgc may be an attractive treatment option not only in Thailand but possibly in other resource poor countries where the high cost of therapy limits access for most infected individuals.
Self-Reported Adherence and Therapeutic Drug Monitoring: Is there a Correlation?
Adherence to antiretroviral therapy is crucial for long term success of HAART. Though therapeutic drug monitoring (TDM) is available for a number of antiretroviral agents, this intervention is more expensive and less accessible than self-report as a measure of adherence. It is important to determine whether patient self-report is correlated with drug levels, since it is so much easier and cheaper to ask patients about their adherence than to draw serum levels.
A group of investigators from the United States explored this issue by obtaining antiretroviral trough levels and self-reported adherence data from 85 HIV infected women followed in the Women’s Interagency HIV Study [Gandhi M, et al. Abstract MoPpB2012]. From October 2000 to April 2001, study participants were asked to recall adherence to their antiretroviral medications over the past 24 hours, 3 days, and 6 months. Additionally, trough levels of PIs and NNRTIs were obtained from each subject. Expected trough levels for each drug were calculated based on the subject’s report of the time of the last dose and published pharmacokinetic data. Results revealed no correlation with 3 day and 6 month adherence by self report, and only a weak correlation with the reported time of last dose (r=-0.28).
It is important to point out that this study has several limitations: they measured only a single drug concentration, the sample included only female subjects, and there was large variability in trough concentrations. Nevertheless, these findings suggest that self-reported adherence is likely to be affected by recall bias: the more time has passed, the less likely it is that patients will be able to provide reliable adherence information.
Nelfinavir and Pharmacogenetics
The role played by pharmacogenetics in antiretroviral pharmacokinetics and response is a hot topic in HIV pharma-cology. Genetic polymorphisms can affect enzymes involved in drug metabolism and result in profound differences in drug exposure between patients. These genetic differences can result in higher drug concen-trations and increased toxicity or excessive drug metabolism, leading to a decreased therapeutic effect.
A genetic polymorphism has been identified in the CYP450 isoenzyme, CYP2C19. This isoenzyme is responsible for the formation of M8, the major active metabolite of nelfinavir (NFV). Though a substantial proportion of Asians are poor metabolizers using CYP2C19, it has not been clear whether NFV and M8 concentrations are affected in this population.
Kuwahara and colleagues from Japan measured NFV and M8 concentrations in 48 HIV infected Japanese patients treated with NFV-containing regimens [Abstract TuPeB4550]. Plasma samples were obtained from subjects treated with NFV for at least two weeks who were not taking other drugs known to affect CYP2C19 or 3A4. Eight subjects were receiving NFV 750 mg tid and the remainder 1250 mg bid. Pharmaco-kinetic sampling was obtained at trough (49 samples) and 4 hours after the morning dose (50 samples). Table 1 shows the pharmacokinetic parameters obtained in this study compared to historical data. Overall, NFV concentrations were higher and M8 concentrations lower than those seen in predominantly Caucasian populations. The authors found that 22% of the patients had undetectable M8 levels. Ninety percent of the patients with undetectable M8 levels had higher NFV plasma concentrations than their counterparts with normal M8 concen-trations. No patient discontinued NFV within one year of therapy because of toxicity. Reasons for discontinuing NFV therapy beyond one year were fatigue (2), diarrhea (2), lipodystrophy (12), and rash (14). No relationship was found between NFV-associated adverse events and NFV concentrations or M8/NFV ratios.
This is the first study to suggest that a genetic polymorphism might affect concentrations of an antiretroviral drug. Unfortunately, the authors failed to determine the enzyme genotype or phenotype of the participants to determine whether the poor metabolizer status was due to 2C19 deficiency. Still, this study introduces the potential role of pharmacogenetics in antiretroviral metabolism and points out the potential importance of genetic polymorphisms as a cause of altered antiretroviral concentrations.
• Didanosine EC–Methadone: It is known that co-administration of the original buffered tablet formulation of didanosine (ddI) with methadone results in up to a 52% reduction in the ddI AUC without effecting methadone pharmacokinetics. One question that has been frequently asked is whether methadone would have a similar effect on the pharmacokinetics of the new enteric coated (EC) formulation of ddI. Gerry Friedland and colleagues presented results of an open-label randomized two-way crossover study in which HIV negative subjects on chronic methadone mainten-ance were randomized to receive ddI EC or the buffered formulation (400 mg PO qd) [Abstract TuPeB4548]. Each formulation was given for two days and then followed by pharmacokinetic sampling over 24 hours. At the end of the study, 15 subjects had completed both treatments. The authors reported a mean Cmax that was 12% lower and an AUC that was
22% higher for the EC formulation compared with the buffered tablets. The relative bioavailability of the EC formulation was 122% higher than that of buffered tablets, possibly explaining this result. Subjects receiving the buffered tablets had a decreased ddI AUC (2633 ng-hr/mL) and Cmax (1554 ng/mL) when compared to historical data obtained from patients treated with ddI who were not receiving methadone (AUC 3136-3489 ng-hr/mL and Cmax 1838-2321 ng/mL), confirming previous results. On the other hand, the pharmacokinetic parameters for study participants treated with the EC formulation (AUC 3062 ng-hr/mL and Cmax 1196 ng/mL) were comparable to historical data in patients not taking methadone (AUC 2562-3578 ng-hr/mL and Cmax 794-1427 ng/mL). Based on these results, the authors recommended that HIV infected patients on chronic methadone should be
treated with the EC formulation of ddI.
• Triple PIs: Lopinavir/Ritonavir Plus Saquinavir: Stephan and colleagues assessed pharmacokinetic interactions at steady state between LPV/r (400/100 mg bid) combined with SQVsgc (1000 mg bid) compared with SQV/RTV (1000/100 mg bid) [Abstract TuPeB4561]. The median Cmin for LPV (5500 ng/mL) and SQV (181-216 ng/mL) was 2-fold greater than the IC95 for susceptible HIV in all cases. The median RTV concentration was lower in subjects treated with LPV/r/SQV. However, the boosting effect of RTV was comparable in the two groups. LPV plasma concentrations were not affected by SQV. The authors concluded that LPV/r effectively boosts SQV concentrations, and that it is unnecessary to add RTV to this regimen.
• Indinavir and Ritonavir: Comparison of Two Regimens: Gerber and colleagues from the AIDS Clinical Trials Group presented results from a pharmacokinetic study comparing two indinavir/ritonavir (IDV/RTV) combination regimens [Abstract TuPeB4552]. Forty-four HIV infected subjects who had failed their first PI-containing regimen (amprenavir, nelfinavir, saquinavir, or saquinavir/nelfinavir), were randomized to receive IDV/RTV at a dose of either 800/200 mg bid or 400/400 mg bid. Twelve hour pharmacokinetic sampling was obtained at steady-state (2 weeks). Two subjects were excluded from the final analysis due to incorrect dosing and undetectable IDV levels. The authors found that the AUC0-12h) and Cmax of IDV was higher in the 800/200 mg arm (AUC0-12h) 38.2 µg/h/mL and Cmax 6309.1 ng/mL) compared with the 400/400 mg arm (AUC0-12h) 23.0 µg/h/mL and Cmax 3633.0 ng/mL). On the other hand, trough (C12h)) was comparable in both groups. The authors conclude that if the trough concentration is the important pharmacokinetic parameter in suppressing HIV, then these two regimens should have comparable anti-HIV effect, but the risk of nephrolithiasis may be greater with the the 800/200 dosing regimen. The authors also observed that the concentrations of IDV and RTV were lower on average in the HIV infected subjects when compared with historical data from healthy volunteers. One possible explanation was a difference in medication adherence monitoring in the two populations. The healthy volunteer group received medications under direct super-vision during the entire study, while in the current study observed doses only occurred during pharmacokinetic sampling.
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