Clinical Pharmacology Update

Hopkins HIV Report 2006 May; 18(3):1-7

Adriana Andrade, M.D., M.P.H.
Johns Hopkins

Clinical pharmacology received substantial attention during the 13th CROI, and several studies presented at this conference increased our understanding of drug interactions, therapeutic drug monitoring, and the pharmacokinetics of antiretrovirals in pregnancy. Discussed below are selected presentations from the conference.

Drug Interactions
Tipranavir, Etravirine, and Darunavir

Protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) undergo metabolism through the cytochrome P450 (CYP450) pathway and can also inhibit and/or induce these enzymes, making them susceptible to clinically significant pharmacokinetic interactions. Because PIs and NNRTIs are often combined in salvage regimens, it is important to understand drug interactions among these agents. Tipranavir (TPV), the PI most recently approved by the FDA, is a substrate, inhibitor, and potent inducer of the CYP3A4 enzyme and also induces the drug efflux pump P-glycoprotein (P-gp). TPV markedly lowers the plasma concentrations of several PIs; therefore, its co-administration with other PIs is contraindicated [Walmsley S, et al. Int Conf AIDS. 2004 Jul 11-16;15:Abstract No. WeOrB1236]. Etravirine (TMC125), a second-generation investigational NNRTI, is a substrate of both CYP3A4 and P-gp. Although TPV does not seem to affect the metabolism of any currently approved NNRTIs, the drug interaction between etravirine and TPV has not been characterized.

Schöller and colleagues evaluated the safety and pharmacokinetics of etravirine when coadministered with ritonavir (RTV)-boosted TPV (TPV/r) [Schöller M, et al. Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 583]. In their study, 24 healthy subjects (19 males, 5 females) first received etravirine 800 mg bid for 8 days, followed by a 14-day washout period. They were then subdivided in two groups of 12 each. In group I, subjects received TPV/r 500/200 mg bid from day 1 to 16, then etravirine 800 mg bid from day 9-16. In group II, participants were given TPV/r 500/200 mg bid from day 1 to 16, then etravirine 800 mg bid from day 1 to 8. The etravirine steady-state mean AUC_12h decreased by 76% and C_min by 82% when co-administered with TPV/r compared to when given alone. TPV and RTV AUC_12h increased by 18% and 23%, respectively. Thirty-eight percent of the subjects discontinued study treatment because of drug toxicity, and 25% of the discontinuations occurred during the TPV treatment period.

These results probably reflect the induction of P-gp and hepatic CYP3A4 activity by TPV, with consequent effects on etravirine metabolism. Given the significant reduction in etravirine plasma concentration that was produced by coadministration of TPV, this NNRTI joins the list of antiretroviral agents that cannot be given with TPV. This is unfortunate, given the need to identify additional drugs for PI/NNRTI combinations that could be used for the treatment of treatment-experienced patients.

A second poster described the pharmacokinetic interactions between etravirine and darunavir (TMC114/r), a second-generation investigational PI. Like etravirine, darunavir is a substrate of CYP3A4 and P-gp, and it can also induce the CYP3A4 pathway; consequently, there is considerable potential for drug interaction when these two agents are combined. Boffito and coworkers conducted an open label steady-state study to evaluate the pharmacokinetic parameters and safety profile of combined etravirine and darunavir given with at least 2 NRTIs, with or without enfuvirtide (ENF, T20) in 10 multi-class experienced HIV-infected patients [[Boffito M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 575c].

Etravirine did not significantly alter the pharmacokinetic parameters of darunavir, and there was a modest reduction in etravirine exposure when compared to historical control data. Etravirine pharmacokinetic parameters were also comparable to historical data from patients taking etravirine with boosted PIs. All patients achieved a decrease in plasma HIV RNA of at least a 2 log₁₀ at week 6, and co-administration of etravirine and darunavir was safe and well tolerated.

Although limited by their small sample size, these results suggest that etravirine and darunavir in combination do not cause harmful pharmacokinetic interactions, making these two drugs good candidates for salvage therapy, a strategy that is now being studied in the Tibotecsponsored DUET studies.

Lopinavir/Ritonavir and Tipranavir

Harris and colleagues explored dose adjustment strategies to overcome the drug interaction between lopinavir/ritonavir (LPV/r) and TPV [Abstract 584]. In their study, 13 HIV-infected subjects on a stable regimen of LPV/r 400/100 mg bid (no other PIs or NNRTIs) added TPV and RTV with or with out additional LPV/r to their regimens, as shown in Table 1; drug concentrations were measured on day 1, pre-dosing and again on day 14. LPV trough concentrations in both groups on day 14 were not statistically different from those on day 1, although substantial interpatient variability was observed on day 14. TPV concentrations on day 14 were higher in both groups compared to historical controls with standard doses of TPV/r. Adverse events (primarily GI toxicity) were more common in Group B.

Although the increase in the RTV and LPV levels seemed to compensate for the inducing effects of TPV on LPV metabolism, the substantial interpatient variability is of concern. These investigators suggested that TDM could be used to avoid under- or overdosing in patients taking this dual PI combination. However, before the combination of LPV/r plus TPV can be recommended, further prospective studies are needed, especially in light of the current limitations of the therapeutic drug monitoring of antiretroviral agents [Andrade A and Flexner C, HHR 2005;17(3):6]. For now, it may be best to avoid coadministration of these agents and instead employ other better-studied PI combinations.

Atazanavir and Other Protease Inhibitors

The possibility of pharmacokinetic interactions between ATV and LPV surfaces frequently in clinical practice. Paul Pham and colleagues from Johns Hopkins conducted an open-label, steady-state study to evaluate the pharmacokinetics of the combination of ATV and LPV/r [Pham P, et al, Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 585]. Fifteen HIV-negative subjects received ATV/r 300/100 mg qd from day 1-10 (Period I), ATV 300 mg qd + LPV/r 400/100 mg bid from day 11-24 (Period II), and ATV/r 300/100 mg qd + LPV/r 400/100 mg bid from day 25-34 (Period III). The addition of LPV/r to ATV 300 mg during period II resulted in a slight increase in ATV C_min. Boosting ATV with RTV 100 mg in period III did not further increase ATV plasma concentrations. LPV pharmacokinetic parameters in period II were comparable to historical controls on LPV/r 400/100 mg bid, suggesting that ATV 300 mg did not significantly affect LPV plasma concentrations. LPV C_min during period III was 28% higher, but LPV AUC and C_max were not significantly different. LPV and ATV were well tolerated; the only reported adverse event was hyperbilirubinemia. This study indicates that when combining these PIs, the dose regimen used in period II seems to be adequate, and there is little additional benefit and probably a higher risk of toxicity by adding the extra dose of RTV 100 mg used in period III. Further clinical studies in HIV-infected patients will be required before this combination can be recommended. Additionally, the LPV/r capsule formulation was used in this study; further investigation is needed using the new LPV/r tablet formulation.

There is considerable interest in combining ATV with SQV because of the minimal effects of these two PI agents on lipids, their divergent resistance profiles, and data suggesting that the two agents act synergistically in vitro. Investigators from the ASPIRE II study evaluated the pharmacokinetics, tolerability, and safety of ATV/SQV bid as a potentially useful dual-PI, RTV-sparing combination [King J, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 586]. In this open-label, sequential, 3-way crossover study, 16 healthy volunteers underwent three 10-day treatment phases separated by a 10-day washout period using the new SQV tablet formulation (doses are shown in Table 1). The pharmacokinetic parameters for ATV were similar for Periods 2 and 3; the ATV C_max and C_12h were 55% lower and 99% higher, respectively, than for historical controls receiving ATV 400 mg qd. SQV pharmacokinetic parameters were significantly higher in Period 1 than in Periods 2 or 3. Women had significantly higher C_max and AUC_12h values than men for all 3 PIs, even after adjusting for weight (median weight, 84.8 kg for men and 62.3 kg for women).

In this pharmacokinetic study evaluating ATV/SQV dosed twice daily, SQV/ATV 1500/200 mg bid did not generate plasma SQV concentrations comparable to those obtained with SQV/r. However, it is important to note that 75% of the participants on the SQV/ATV 1500/200 mg combination had SQV plasma concentrations above the estimated protein binding-corrected IC₉₅ for SQV (approximately 100 ng/mL). The authors concluded that prospective studies using SQV/ATV 1500/200 mg bid are needed for characterization of the safety, tolerability, and pharmacokinetics of this combination of PIs in antiretroviral naïve patients.

The question of whether gender differences in pharmacokinetics really exist continues to be investigated. While the mechanisms underlying pharmacokinetic sex-based differences did not fall within the scope of this study, these findings are consistent with prior reports suggesting that drug metabolism may differ between sexes [Flexner C. HHR, 2005;17(4):1; Andrade A, Flexner C. HHR, 2004;16(3):1]. However, to date there are no compelling data to justify antiretroviral dose modifications based on sex-related pharmacokinetic differences.

Finally, Clay and colleagues presented the results of a prospective, randomized, 3-way crossover study evaluating the pharmacokinetic interactions between ATV and fosamprenavir (FPV) [Clay P, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 587]. Twenty-one HIV-negative subjects (11 men, 48% non-white) received in random order: FPV 1400 mg qd, ATV 400 mg qd, or ATV 400 mg + FPV 1400 mg qd for 14 days. Treatment arms were separated by 14-day washout periods. ATV significantly enhanced the APV AUC by 78%, while the ATV AUC was reduced by 33% when co-administered with FPV. The FPV/ATV combination is another example of a potentially useful dual-PI therapy with favorable toxicity and resistance profiles. Although this combination resulted in a favorable pharmacokinetic profile for FPV, further prospective studies are needed to evaluate this therapy more thoroughly.

Carbamazepine Plus Efavirenz

Epilepsy is prevalent in HIV-infected patients, and management of this condition involves the use of anticonvulsant agents. Carbamazepine (CBZ), phenobarbital, and phenytoin, are potent CYP3A4 inducers and can lower the plasma concentrations of PIs and NNRTIs that are substrates, inducers, and/or inhibitors of this enzyme. Previous studies have shown that coadministration of phenytoin with nelfinavir (NFV) and LPV/r results in a two-way drug interaction, with reductions in phenytoin, LPV, and NFV plasma concentrations [Shelton, 40th ICAAC, 2003 Abstract 426; Lim ML, et al. Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 535]. Kaul and colleagues reported the results of a study in healthy volunteers that was designed to determine whether a pharmacokinetic drug interaction occurs between efavirenz (EFV) and CBZ [Boffito M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 575c].

The investigators found a two-way drug interaction in which EFV decreased the CBZ AUC_24h, C_max, and C_min by 27%, 20%, and 35%, respectively, and CBZ decreased the EFV, and C_min by 36%, 21%, and AUC_24h, C_max47%, respectively. These results illustrate the complexity of drug interactions involving CYP450 inducers and substrates. In this case, EFV and CBZ are inducers and substrates of CYP3A4 and accelerated each other’s clearance, probably by inducing hepatic CYP3A4. The authors did not make any recommendations about dose adjustments to counteract this interaction but suggested use of alternative anticonvulsants not dependent on CYP3A4 metabolism (such as gabapentine and levetiracetam) when concomitant treatment with EFV is needed.

Lopinavir/Ritonavir and Acid-Reducing Agents

Recent data on the profound reduction in ATV concentration associated with coadministration of the proton pump inhibitor, omeprazole, have raised concerns that suppression of gastric acid secretion could also affect the bioavailability of other PIs. Researchers from Abbott Laboratories presented results of a multiple-dose, open-label, pharmacokinetic interaction study in 71 healthy volunteers that compared the new melt-extrusion LPV/r tablet formulation, ATV/r, omeprazole, and the H2 antagonist, ranitidine [Chen K, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 578]. LPV bioavailability was not affected by either omeprazole or ranitidine, which is not surprising, given that the solubility of LPV is not pH-dependent. Plasma concentrations of omeprazole and ranitidine were comparable to historical control values. ATV C_max and AUC_12h decreased by 48% and 65%, respectively, reinforcing the notion that ATV absorption is affected by acid-lowering agents.

Lopinavir/Ritonavir and Rosuvastatin

Hyperlipidemia is a common adverse event in PI therapy. A number of HMG Co-A reductase inhibitors (“statins”) undergo hepatic CYP3A4 metabolism, resulting in pharmacokinetic drug interactions when these agents are combined with PIs and NNRTIs. Inhibition of CYP3A4 by SQV/r significantly increases simvastatin and atorvastatin concentrations, while induction by EFV reduces simvastatin and atorvastatin levels. CYP3A4 induction can produce subtherapeutic levels, potentially reducing the effectiveness of these drugs, while inhibition can result in higher plasma concentrations and cause serious drug toxicity. [Fichtenbaum CJ, et al. AIDS. 2002 Mar 8;16(4):569-77; Gerber et al. J Acquir Immune Defic Syndr. 2005 Jul 1;39(3):307-12].

Investigators from the Netherlands evaluated the effects of rosuvastatin on LPV plasma concentrations (and vice versa) in 22 HIV-infected patients [Van Der Lee M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 588]. Subjects were treated with rosuvastatin 10 mg qd for 12 weeks, and rosuvastatin dose escalation was undertaken to 20 or 40 mg if predetermined fasting target lipid values were not met. Treatment with rosuvastatin did not alter LPV plasma concentrations. However, the median rosuvastatin trough concentrations for 10, 20, and 40 mg were 1.5, 1.6, and 1.9 times higher, respectively, than for historical controls. This finding was surprising, given that rosuvastatin does not undergo CYP3A4 metabolism. Unfortunately, the design of this study made it impossible to identify the mechanism for the observed drug interaction. Nevertheless, it is reassuring that the magnitude of the change in the rosuvastatin trough concentrations was significantly lower than the 25-fold and 74% increases in simvastatin and atorvastatim concentrations, respectively, when used in combination with PI therapy.The minimal increase in rosuvastatin concentrations suggests that this statin is probably a safe choice for coadministration with PIs.

Enfuvirtide and Tipranavir/Ritonavir

TPV and enfuvirtide (ENF) are common components of salvage regimens. Investigators from Italy examined whether co-administration of ENF 90 mg SQ bid with TPV/r would affect the steady-state pharmacokinetics of TPV and RTV [Gonzalez De Requena D, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 579]. Thirty-nine HIV-infected patients were studied: 20 on TPV/r- and ENF-containing regimens and 19 on TPV/r without ENF. TPV and RTV trough concentrations were higher in the presence of enfuvirtide, which is surprising, since ENF is not a known CYP450 inducer, inhibitor, or substrate. Although at present there is no biological explanation to support these findings, the investigators hypothesized that a higher volume of distribution and elimination half-life for both PIs in the presence of enfuvirtide could explain their results. It is important to point out that limitations in the study design could also have affected the results, which will need to be confirmed in future studies.

Lopinvir/Ritonavir, Efavirenz, and Hemodialysis

Gupta and coworkers conducted a prospective, observational study to evaluate the steady-state pharmacokinetics of EFV and LPV in HIV-infected patients undergoing hemodialysis [Gupta S, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 573]. Twenty-six subjects (13 per arm) on stable LPV/r or EFV-containing regimens underwent a full pharmacokinetic sampling on a non-dialysis day. EFV and LPV/r AUC values were equivalent to those in historical controls with normal renal function who had received the same formulations of EFV and LPV/r.There was substantial variability in EFV pharmacokinetics, and pharmacogenomic evaluation is ongoing to determine whether genetic polymorphism could explain these results. LPV pharmacokinetic parameters were modestly lower in HD patients compared to historical controls, and protein binding evaluations are pending. It is important to note that the LPV/r capsule formulation was used in this study, and further investigation is warranted with the new tablet formulation. Overall, these findings suggest that dose adjustments for these two antiretroviral agents are not necessary in patients on hemodialysis.

Lopinavir/Ritonavir and Tenofovir

Co-administration of LPV/r and tenofovir disoproxil fumarate (TDF) results in a 30% increase on tenofovir plasma concentrations. Although this raises concerns about drug-induced toxicity, to date, there is no clinical evidence of increased TDF toxicity in patients taking PIs. The mechanism underlying this interaction is unclear. Investigators from the University of Colorado presented data regarding the effects of LPV/r on the clearance of tenofovir, in an attempt to shed some light on the mechanism of this drug interaction [Kiser J, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 570]. Thirty HIV-infected adults (73% males, 20% black) with a mean age of 42 (GFR>60 mL/min, no hypertension, diabetes, or hepatitis C) and on a stable TDF-containing regimen were enrolled into one of two groups: Group 1 received TDF 300 mg qd + LPV/r 400/100 mg bid + other NRTI; Group 2 received TDF 300 mg qd + other NRTI or NNRTIs but no PIs. After adjusting for estimated GFR, the tenofovir clearance was 1.16 times greater in subjects not taking a PI than in those taking LPV/r. Weight, CD4, serum creatinine, and estimated GFR were comparable between the two groups, suggesting that interactions between these two drugs occur at the renal level.

Therapeutic Drug Monitoring

The use of therapeutic drug monitoring (TDM) for antiretrovirals continues to be debated by the pharmacology community and has been reviewed in several issues of the Hopkins HIV Report [Flexner C, HHR 2002;2:1, Flexner, C, HHR 2000;12(2):5]. Several presentations at CROI attempted to shed more light on this controversial topic.

TDM studies for antiretroviral-experienced subjects have employed a variety of ratios that combine the patients’ drug concentrations and resistance mutations to correct drug doses above or below a desired therapeutic level [Flexner C. HHR 2002;(14)3:6]. Bonora presented the results of a prospective study investigating whether the virological response to TPV was associated with TPV genotypic inhibitory quotient (gIQ), defined as the ratio between the mean of all available TPV C_trough concentrations and the number of TPV-associated mutations [Bonora S, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 577]. Twenty-seven heavily antiretroviral-experienced patients treated with TPV/r 500/200 mg bid + 2 NRTIs with or without ENF had C_trough concentrations measured at baseline and weeks 4, 8, and 12, and a VircoTYPE analysis was performed at baseline. Optimized background score (OBS), defined as the number of active drugs in the regimen based on resistance test results, was also used to assess virologic response to ENF. By logistic regression analysis, TPV gIQ was the only predictor of viral suppression at 12 weeks; OBS, TPV C_trough, and the number of TPV mutations were not predictive. At 12 weeks, the viral load had fallen by 2.15 log, and 40.7% of the patients had an undetectable viral load. The TPV gIQ EC₅₀ at week 12 was 13,000 (50% probability of reaching an undetectable viral load at week 12); 7/9 subjects with a TPV gIQ >13,000 and 4/18 with a TPV gIQ <13,000 had an undetectable viral loads at that time point.

This study reinforces the notion that drug concentrations alone are poor predictors of virological outcomes in patients with complex treatment histories. Integration of viral susceptibility into the interpretation of drug levels is crucial when using TDM in this population.

Podsadecki and colleagues described the effects of “white coat compliance” (improved adherence immediately preceding a clinic visit) on TDM estimates [Podsadecki TJ, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 590]. These investigators studied 178 antiretroviral-naïve subjects enrolled in a randomized, open-label trial comparing the efficacy, tolerability, and safety of LPV/r qd or bid plus emtricitabine (FTC) plus TDF. They monitored adherence to LPV/r using MEMS caps and measured LPV plasma concentrations during weeks 3, 8, 16, 24, and 48. In a majority of the patients (66%), adherence was >95% (defined as “perfect adherence”) in 31% of the clinic visits for pharmacokinetic sampling, but only in the 1-3 days immediately prior to that visit; outside that window, adherence was <95%. These findings suggest that patients could have had therapeutic drug concentrations on days of pharmacokinetic sampling, even though their adherence during most of the study duration was below the 95% cutoff level. These results might explain detectable viremia in patients who are reportedly adherent to HAART and have therapeutic drug concentrations. They underscore the limitations of TDM, challenging the potential utility of this approach in predicting long-term exposure to drug concentrations.

In an attempt to identify factors that could influence antiretroviral pharmacokinetic parameters used in the TDM of antiretrovirals, Ghandi and collaborators performed full pharmacokinetic samplings of PIs and NNRTIs in HIV-infected women enrolled in the Women’s Interagency HIV Study [Gandhi M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 592]. In this study, 99, 76, and 115 patients, respectively, were on NVP-, EFV-, and LPV/r-containing regimens. Doubling the AST and ALT increased the EFV AUC by 37% and 28%, respectively while doubling the AST and ALT increased the NVP AUC by 23% and 24%, respectively. Women co-infected with hepatitis C who had impaired renal function had 1.23- and 1.38-fold higher NVP AUCs, respectively, compared to their HCV-negative counterparts with normal renal function. An increase in fat-free mass was associated with an increased NVP AUC, while an increase in body weight was associated with a reduction in EFV and LPV AUCs. Fluconazole therapy was associated with a 3.5-fold increase in the EFV AUC, while use of St. John’s wort, anticonvulsants, or rifamycin decreased the LPV AUC by 47%.

As we learn more about the TDM of antiretrovirals, it is becoming clear that this analysis is considerably more complex than simply measuring drug plasma concentrations. Interpretation of TDM results is also challenging, as it can be influenced by a number of factors prevalent in HIV-infected patients (e.g., those identified by Gandhi and colleagues). We recently learned that there is a significant degree of intra- individual variability in antiretroviral concentrations that could produce misleading TDM results [Nettles R, et al. Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 642]. The factors identified in this study certainly underscore the complexity of TDM use in this population and reinforce the need for large prospective trials to advance our understanding of the usefulness of this practice.

Pharmacokinetics of Antiretroviral Agents in Pregnancy

Physiologic changes during pregnancy may affect the pharmacokinetics of antiretroviral agents as a result of changes in protein binding, plasma volume, excretion, and metabolism. These changes are important to assess, as achieving therapeutic plasma concentrations of antiretroviral drugs is critical for prevention of HIV mother-to-child transmission and for maintaining appropriate control of maternal infection. Several presentations addressed this important issue.

Khuong-Josses reported on the results of a pharmacokinetic study in a cohort of French HIV-infected pregnant women (35 black, 3 white, 2 Asian) receiving nelfinavir (NFV)-containing regimens [Khuong-Josses M-A, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 707]. NFV trough concentrations were measured 2 weeks after treatment initiation and during the second and third trimester of pregnancy. NFV was administered at 1250 mg bid or 750 mg tid in 36 and 4 women, respectively; dietary counseling was provided throughout the study. Eighteen of the 40 women (42%) did not achieve NFV target trough concentrations (1.27±0.86 vs 1 ng/mL). Women with NFV concentrations below the target trough appeared to experience a lower decline in viral load than did their counterparts, although this was not statistically significant. Although the dose was increased to 1500 mg bid in 8 of these 18 women, the NFV trough remained below 1 ng/mL in 2 of them. Viral load decreased from 4.12 log₁₀ to 2.02 log₁₀ c/mL after a median of 15 days of treatment and was undetectable in 25 of 37 women at the time of delivery; no vertical transmission occurred during the study.

Two studies presented at the 13th CROI examined LPV plasma concentrations in pregnant, HIV-infected women. [Mirochnick M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 710] reported on the follow-up to the PACTG 1026 study first presented at the XV International AIDS Conference in Bangkok, showing that standard LPV/r dosing during the third trimester of pregnancy resulted in reduction of approximately 50% in LPV plasma concentrations compared to the postpartum period [Stek A, et al. Int Conf AIDS. 2004 Jul 11-16;15:Abstract No. LbOrB08]. The recent, prospective, non-blinded study included a cohort of pregnant women receiving standard dosing of the gel capsule formulation of LPV/r 400/100 mg bid (n=8) during the second trimester and 533/100 mg bid (n=26) during the third trimester and first 2 weeks postpartum (n=22). Intense steady-state pharmacokinetic sampling was performed during the third trimester and postpartum period and was optional in the second trimester. As shown in Table 3, LPV AUC_12hr and C_min were lower during the second trimester of pregnancy than in the third trimester and postpartum period. It is also important to note that LPV concentrations were significantly higher during the postpartum period, probably reflecting a return to antenatal physiology. The higher dose of LPV/r was well tolerated, and viral load was <400 c/mL in 23/24 women at delivery. A study to evaluate the new LPV/r tablet formulation is planned.

Lyons and colleagues measured steady-state LPV trough concentrations in 16 women in their third trimester receiving standard doses of, LPV/r capsules combined with an NRTI backbone (zidovudine/lamivudine or tenofovir/lamivudine) [Lyons F, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 709]. Adherence was monitored throughout the study, and the use of medications known to interfere with LPV metabolism was prohibited. The median trough concentrations of LPV were 3660 ng/mL; 15 women (94%) met the minimum LPV trough concentration for inhibiting wild-type virus (1000 ng/mL). Viral load was undetectable in 14 of 16 women; the two with detectable virus were felt to have inadequate adherence. There were no cases of vertical transmission.

While the sample sizes were small in all three studies presented, the results of two of these studies suggest that physiological changes during pregnancy can significantly affect drug pharmacokinetics. Limitations with the NFV study design could have affected the findings. For example, inclusion of a small number of patients on NFV three times daily, which has been shown to produce variable and generally lower plasma concentrations of NFV in pregnancy compared to twice daily dosing, might have affected viral load decline. It is also important to point out that both LPV/r studies were performed using the capsule formulation, so their currently applicability is unknown. A follow up study with the new tablet formulation is in development by Mirochnick and colleagues. Overall it remains unclear whether these differences in plasma concentration significantly affect the efficacy of antiretroviral agents in preventing HIV mother-to-child transmission or in controlling maternal viral load. Currently there are insufficient data to support a recommendation to use increased doses of NFV or LPV/r in pregnant women as an attempt to compensate for the physiological pharmacokinetic changes that occur during pregnancy. Further prospective studies are needed to guide clinical practice.

2006-05-10
HHR-2006-05-01

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