Pharmacokinetic Interactions Between Ritonavir-Boosted Darunavir and NNRTIs: A Report of 3 Cases

Management of treatment-experienced patients with multidrug resistance can be challenging. Fortunately, since 2006, 4 new antiretroviral agents-darunavir, maraviroc, raltegravir, and etravirine-with activity against drug-resistant HIV have been approved. Notably, 3 of these 4 new agents-all but raltegravir-are metabolized by and influence the cytochrome P-450 (CYP) system. In this regard, they are similar to existing protease inhibitors (PIs) and NNRTIs. This extraordinary period in HIV drug development has led to a significant increase in the proportion
of treatment-experienced patients achieving virological suppression.¹

We recently encountered 2 patients with extensive PI resistance who had never received NNRTI therapy. For these patients, a regimen of ritonavir-boosted darunavir (DRV/r) and efavirenz or nevirapine was considered. A third patient was a candidate for treatment with DRV/r and the NNRTI etravirine. A review of these cases serves as a backdrop against which to discuss the potential pharmacokinetic in­teractions when coadministering DRV/r-a boosted PI with demonstrated efficacy in patients with PI resistance^2-5-and the 3 NNRTIs now in widest clinical use.

CASE SUMMARIES
Disease characteristics and resis­tance profiles for the 3 case patients are described in Table 1. All had long-standing HIV infection, with a mean 15 years since diagnosis and 5 or more years of virological failure on a PI-containing regimen. The mean baseline CD4⁺ cell count was 214/µL and mean plasma HIV RNA level was 19,142 copies/mL. All 3 patients had extensive genotypic evidence of PI and NRTI resistance (a mean of 9 NRTI and 11 PI mutations). Of note, 2 of the patients had been maintained on long-term failing therapy with indinavir, an agent no longer considered a preferred or alternative option for initial therapy.⁶ Also, 2 patients were NNRTI-naive, and the third, who had been previously treated with efavirenz, had 3 NNRTI mutations.

Case 1
A 53-year-old woman was referred for evaluation of multidrug-resistant HIV infection with a CD4⁺ cell count of 185/µL (CD4%, 23) and an HIV RNA level of 27,807 copies/mL. She had been given a diagnosis of HIV infection 15 years earlier and had initially received dual-NRTI therapy consisting of stavudine and lamivudine, followed by a regimen of in­dinavir, stavudine, and lamivudine for nearly 10 years. Her plasma HIV RNA level had never been fully suppressed. In 2004, an HIV genotype revealed multiple thymidine analogue–associated mutations and another NRTI mutation, M184V, as well as 12 PI mutations. She was offered an enfuvirtide-based regimen but refused. The decision was therefore made to maintain the current failing regimen and avoid exposure to the NNRTI class in anticipation of newer antiretroviral options. The NRTI component of her regimen was ultimately changed to coformulated tenofovir/emtricitabine to reduce further risk of lipoatrophy.

A phenotype was requested 3 months before referral and confirmed susceptibility to the NNRTI class but with extensive PI resistance except for preserved susceptibility to tipranavir. (This test was performed before the availability of darunavir testing.) At the time of referral, the patient acknowledged that she had chosen to discontinue indinavir in the preceding months because of lipoatrophy and thus had been taking only 2 NRTIs.

Despite high-level PI resistance, the presence of only 1 major and 1 accessory darunavir-associated mutation predicted a favorable response to this PI (Table 2).^7-9 Therefore, when darunavir became available in June 2006, a regimen of DRV/r 600/100 mg twice daily, efavirenz 600 mg once daily, and coformulated ten­ofovir/emtricitabine 300/200 mg once daily was started. The patient tolerated the new regimen well, without notable adverse effects, and achieved virological suppression within 4 months.

Case 2
A 48-year-old man with bipolar disorder and drug-resistant HIV infection was referred for recommendations regarding antiretroviral therapy options. His HIV infection was diagnosed in 1990, and he was subsequently treated with zidovudine monotherapy, followed by the addition of didanosine. In 1996, the regimen was switched to indinavir plus stavudine and lamivudine. At the time of referral in June 2006, his regimen consisted of indinavir, tenof­ovir, and emtricitabine. Although his HIV RNA level had never been fully suppressed, it had remained relatively low at about 5000 copies/mL. His absolute CD4⁺ cell count, which had consistently been above 200/µL, had recently declined to 128/µL (CD4%, 15).

A resistance phenotype and genotype test (PhenoSense GT, Monogram Biosciences, Inc, South San Francisco) at the time of referral revealed moderate-high–level NRTI resistance (partial susceptibility only to tenofovir and didanosine), but hypersusceptibility to the then-available NNRTIs (efavirenz and nevir­apine); the replication capacity was 9%. Within the PI class, the virus was susceptible to darunavir (fold change, 1.1) and fosamprenavir, with partial susceptibility to tipranavir (fold change, 2.69).

Given its potential for neuropsychiatric adverse effects, efavirenz was considered to be a poor option for this patient with bipolar disease. Since his CD4⁺ cell count of 128/µL was below the threshold of 400/µL considered to confer a greater risk of nevirapine hypersensitivity in men, he was started on a regimen of DRV/r 600/100 mg twice daily, nevirapine 200 mg twice daily (after a 14 day lead-in of 200 mg once daily), and coformulated tenof­ovir/emtricitabine 300/200 mg once daily. After 6 weeks of therapy, his plasma HIV RNA level declined to less than 75 copies/mL.

Case 3
A 49-year-old woman with long-standing virological failure was maintained on a regimen of ritona­vir-boosted fosamprenavir and coformulated tenofovir/emtricitabine while awaiting new therapeutic options. Her HIV infection was diagnosed 12 years earlier (CD4⁺ cell nadir of 73/µL), and she had been treated with numerous antiretroviral combinations, which included 5 different PIs. Despite having a persis­tently detectable HIV RNA level in the range of 5000 to 20,000 copies/mL, her CD4⁺ cell count remained above 300/µL. Although enfuvirtide remained a treatment option, she strongly wished to avoid injections unless her CD4⁺ count declined significantly.

A virtual phenotype/genotype test (vircoTYPE HIV-1, Virco Lab Inc, Bridgewater, NJ) was obtained in March 2007 because access to several new antiretrovirals became available through FDA approval or early access programs. The analysis revealed resistance to all NRTIs. The patient also had resistance to the NNRTIs efavirenz and nevirapine, which was conferred by the K103N mutation (she had received nevira­pine about 10 years before referral). In addition, there was a total of 15 PI mutations, with a reduced response to DRV/r (fold change, 11.4) and rit­onavir-boosted tipranavir (fold change, 1.4). Three darunavir-associated mutations were present: L33F, I54L, and I84V.

Since the only significant NNRTI mutation was K103N, etra­virine susceptibility was preserved. Darunavir was selected as the PI component of the regimen, although full activity was not anticipated given the predicted fold change of 11.4.¹⁰ Tipranavir/ritonavir was not an option because it has been shown to reduce etravirine bioavailability (area under the concentration-time curve) by 76%.¹¹ Finally, raltegravir was added as the second agent for which full activity was expected. Thus, her regimen consisted of DRV/r 600/100 mg twice daily, etravirine 200 mg twice daily, ralteg­ravir 400 mg twice daily, and co-formulated tenofovir/emtricitabine 300/200 mg once daily. After 20 days on this new regimen, the plasma HIV RNA level was below 75 copies/mL and the CD4⁺ cell count had risen to 435/µL.

PHARMACOKINETIC INTERACTIONS WITH SPECIFIC NNRTIs AND DARUNAVIR
Tables 3 and 4 provide a summary of the pharmacokinetic interactions between DRV/r and efavirenz, nevir­apine, and etravirine.

Efavirenz and DRV/r
No prospective clinical studies have evaluated the virological efficacy of efavirenz coadministered with DRV/r. Knowledge of the pharmacokinetic interaction between these agents is derived from data from a study of HIV-negative persons.12 In that study, 12 healthy volunteers received DRV/r 300/100 mg twice dai­ly and efavirenz 600 mg once dai­ly. The medications were first given individually, followed by a period of coadministration. The efavirenz 24-hour bioavailability (AUC_0-24h) was increased by 21% during coadministration with DRV/r. Conversely, the darunavir AUC_0-12h and minimum plasma concentration (C_min) decreased by 13% and 31%, respectively. The combination was well tolerated, and no serious adverse events occurred during the study. It should be noted that the DRV/r dosage used in this study was 300/100 mg twice daily. Studies using the recommended dosage of DRV/r 600/100 mg twice daily are expected to result in similar concentration changes.

The slight increase in efavirenz and decrease in darunavir levels noted in this study are consistent with the CYP3A4 induction and inhibitory effects, respectively, of these drugs. Efavirenz both induces and inhibits CYP3A4, while darunavir is a substrate of CYP3A4. The resultant decrease in plasma darunavir concentrations is consistent with the potent CYP3A4 induction effect of efa­virenz in this setting.

While efavirenz is primarily metabolized by CYP2B6, partial metabo­lism occurs via CYP3A4.^13,14 Although the mechanism has not been fully elucidated, inhibition of CYP3A4 by DRV/r may contribute to the mildly increased plasma efa­virenz concentrations observed in the study of HIV-negative volunteers.¹² Further studies are needed to elucidate the specific mechanisms involved.

The clinical significance of these changes in drug concentration is unknown, and dose adjustment for either darunavir or efavirenz is not currently recommended. However, given the potential for increased exposure to efavirenz, clinical monitoring for CNS toxicity is indicated. Conversely, if darunavir susceptibility is marginal, the reduction in dar­unavir levels by efavirenz might be expected to reduce antiviral efficacy.

Nevirapine and DRV/r
The pharmacokinetic effect of DRV/r and nevirapine coadministration was studied in a randomized crossover trial of 16 HIV-infected patients who were receiving stable nevirapine therapy (200 mg twice daily for 16 or more weeks).¹⁵ When DRV/r 400/100 mg twice daily was given concurrently with nevira­pine in 8 of the patients, the AUC_0-12h, peak plasma concentration (C_max), and C_min of nevirapine were increased by 27%, 18%, and 47%, respectively. Nevirapine is primarily metabolized by CYP3A4 and CYP2B6, although other liver iso­zymes may be involved. In addi-tion, autoinduction of CYP3A4 and CYP2B6 by multidose nevirapine over time results in decreases in ne­virapine's half-life. Therefore, inhibition of CYP3A4 by DRV/r may account for the decreased metabolism and resultant increased nevir­apine levels noted in this study.

Since all patients were receiving nevirapine therapy at baseline in that study,¹⁵ the study investigators used the darunavir concentrations in patients without nevirapine exposure from the TMC114-C137 trial as historical controls.¹⁶ In the TMC114-C137 trial, 8 HIV-negative volunteers received DRV/r 400/100 mg twice daily for 6 days plus a final dose on day 7. Thus, based on between-study comparisons of darunavir concentrations with and without ne­virapine exposure, nevirapine increased the darunavir AUC_0-12h, C_max, and C_min by 24%, 40%, and 2%, respectively. One would expect a reduction in dar­u­na­vir concentrations based on CYP3A4 induction by ne­virapine. However, the role of nevirapine autoinduction in this case is unclear because the effects are concentration-dependent and full-dose nevirapine (200 mg twice daily) was used in the study.

With an increase in the AUC_0-12h of darunavir and nevirapine by 24% and 27%, respectively, the study investigators concluded that the concentration changes were not clinically significant. No dose alterations are recommended when DRV/r and nevirapine are given in combination; however, it should again be noted that a DRV/r dosage of 400/100 mg twice daily was used instead of the currently approved dosage of 600/100 mg twice daily for treatment-experienced patients. Thus, as with concomitant use of darunavir and efavirenz, the clinical experience of darunavir combined with nevir­apine is limited, but the risk of increased adverse effects in the setting of coadministration appears to exist.

Etravirine and DRV/r
The NNRTI etravirine received FDA approval on January 18, 2008, and has activity against both wild-type virus and several NNRTI-resistant viral strains, including those harboring the K103N mutation.^17-20 In addition, clinical trials of etravirine in patients with current or historical resis­tance to NNRTIs have shown that etravirine plus an optimized background regimen containing darunavir is more effective than the background regimen alone.^21-23 Etra­virine is a diarylpyrimidine analogue that was specifically designed to have a higher genetic barrier to resistance than other available NNRTIs.²⁴ The structural flexibility of etravirine allows it to bind the reverse transcriptase enzyme in multiple conformations, thereby preserving antiviral activity against some reverse transcriptase mutations.²⁵

The pharmacokinetic interaction between DRV/r and etravirine was investigated in a crossover trial of 32 HIV-negative volunteers.^26,27 All volunteers initially received etravirine 100 mg twice daily for 8 days, followed by a wash-out period of at least 14 days. DRV/r 600/100 mg twice daily was then administered for 16 days with etravirine at a dosage of either 100 or 200 mg twice daily, given concurrently during the final 8 days of therapy.

Coadministration of etravirine 100 mg with DRV/r decreased the AUC_0-12h, C_max, and C_min of etravirine by 37%, 32%, and 49%, respectively. The effect on darunavir levels was negligible, with an increase in darunavir's AUC_0-12h, C_max, and C_min of 15%, 11%, and 2%, respectively.

The study authors noted that increasing the dosage of etravirine to 200 mg twice daily during the coadministration phase of the study resulted in an increase in etravirine AUC_0-12h and C_min of 80% and 67%, respectively. However, this is in comparison to the levels attained with etravirine monotherapy at a dosage of 100 mg twice daily. Without baseline data for the FDA-approved dosage of etravirine-200 mg twice daily-it is difficult to interpret the pharmacokinetic effects of coadministration in the context of this study. By comparing the results with historical control data, the authors concluded that etravirine 200 mg twice daily can be administered with DRV/r without dose adjustment.^26,27

Another study assessed the pharmacokinetics of etravirine 200 mg twice daily and DRV/r 600/100 mg twice daily in 10 HIV-infected persons with highly resistant virus. The findings were similar to those of the crossover study of HIV-negative volunteers: plasma exposure to dar­unavir was similar to that in historical control patients taking dar­unavir without etravirine. In addition, etra­virine levels in the study participants were reduced by about 30% in the setting of coadministration compared with the etravirine levels in historical controls. This was not considered to be clinically significant because the C_min was higher than the median inhibition concentration for HIV wild-type virus.^28,29

Etravirine is a substrate for CYP3A4, CYP2C9, and CYP2C19; an inducer of CYP3A4; and an inhibitor of CYP2C9, CYP2C19, and P-glycoprotein. Thus, the mechanism by which DRV/r reduces etravirine levels remains uncertain, because one would predict that CYP3A4 inhibition by DRV/r would result in the converse effect. However, it is pos­sible that factors affecting drug absorption or metabolism, such as drug transport proteins or pharmacogenomic factors, are not currently fully appreciated. It should be noted that food increases the bioavailabil­ity of etravirine,³⁰ and it is recommended that etravirine be taken with food.

Although the AUC_0-12h of etra­virine was reduced by 37%, the combination of DRV/r and etravirine was found to be effective in 2 large clinical trials.^21,28,29 Furthermore, pooled analysis of the week 24 DUET-1 and DUET-2 results found no link between etravirine pharmacokinetics and its efficacy or safety.³¹ As a result, the authors concluded that etravirine and DRV/r can be coadministered without dose adjustment.³⁰

Since patients may be immediately switching from a failing efa­virenz-based regimen to one containing etravirine, a potential drug-drug interaction could arise if the enzyme induction by efavirenz were to influence etravirine levels. No formal pharmacokinetic data are available to address this issue. However, because etravirine takes approximately 7 days to achieve steady-state concentrations (the half-life of etra­virine is approximately 41 hours³⁰), it is likely that enzyme induction properties associated with the discontinued efavirenz will be diminished significantly over this time (unpublished data, Tibotec Pharmaceuticals, 2008). Thus, steady-state levels of standard-dose etravirine may very well be similar to those in a patient who had not been taking efavirenz immediate­ly before receiving etravirine. A study is currently ongoing that will address this possible efavirenz-etra­virine interaction.

CONCLUSIONS
For patients with highly drug-resis­tant HIV infection, the development of novel therapies in both existing and new drug classes marks an exciting time for patients and clinicians alike. Several recent studies^{2-4,21,22,32,33} suggest that a majority of treatment-experienced patients can now be expected to achieve sustained virological suppression de­spite extensive PI and NNRTI resistance, with response rates comparable with those seen in treatment-naive patients from the late 1990s.

We have described 3 patients with extensive PI and NRTI resis­tance who achieved virological suppression on regimens containing an NNRTI plus DRV/r. In 2 of the 3 patients, the virological suppression achieved was most likely because of the activity of the NNRTIs and DRV/r, since the NRTI component used was significantly compromised by resistance mutations. In the third case, the use of the integrase inhib­itor raltegravir contributed an additional active drug, and the contribution of the DRV/r individually cannot be determined.

Despite alterations in plasma concentrations of both darunavir and the NNRTI during coadministration, the package insert for dar­unavir does not recommend dose adjustment. However, the knowledge of pharmacokinetic trends does provide insight into and understanding of what to expect in certain clinical situations in which patients may be more vulnerable to adverse effects or inadequate antiviral activity. These would include the potential for efavirenz-related CNS toxicity in someone with baseline neuro­psychiatric disease; the potential for decreased etravirine effectiveness with 1 or 2 etravirine-related mutations; and the potential for reduced darunavir activity in cases of marginal predicted activity based on resistance testing.

While the published clinical data on the use of etravirine with DRV/r is extensive,^5,21 information on the use of this boosted PI combination with the NNRTIs nevirapine and efavirenz is much more limited. In the POWER studies, all patients who received darunavir already had resistance to nevirapine and efa­virenz.^2,3 In the TITAN study, an efavirenz-based optimized background regimen was used with darunavir in only 9% of study participants, and 2% used nevirapine.⁵ As a result, information on the coadministration of these NNRTIs with darunavir will come largely from the pharmacokinetic studies in healthy volunteers cited here.

For patients whose antiretroviral history and resistance profile allow treatment with DRV/r plus an NNRTI (in addition to other select agents), the combination may be a highly effective option. Although pharmacokinetic data suggest that dose adjustments are not necessary when DRV/r is given in combination with any of the currently available NNRTIs, understanding pharmacokinetic trends allows clinicians to gauge the potential for adverse effects as well as regimen potency and thus provide the maximum chance for regimen success.

Dr Sax reports consulting for Abbott, Bristol-Myers Squibb, Gilead, and GlaxoSmithKline; receiving grant support from GlaxoSmithKline and Pfizer; and receiving honoraria for teaching from Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, and Tibotec.

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