Other drug interaction studies at ICAAC

31 December 2009. Related: Conference reports, PK and drug interactions, ICAAC 49th San Fransisco 2009.

HIV-druginteractions.org

These summaries are selected from a longer report published by this group on the Liverpool University site. All references are to the Programme and abstracts for the 49th ICAAC, 12-15 September 2009, San Francisco.

Interactions with vicriviroc

Drug interactions with vicriviroc (30 mg alone or with RTV) were studied in HIV-negative volunteers.

There was no effect on midazolam when administered with vicriviroc alone, but there was a marked increase when administered with ritonavir. Ketoconazole increased vicriviroc AUC by 136% when administered alone and by 503% when administered with ritonavir.

There was no effect on vicriviroc exposure with rifabutin when administered with ritonavir (200 mg once daily). Rifampicin markedly decreased vicriviroc exposure when coadministered with RTV (100 mg twice daily) – the relative oral bioavailability was 11.6% based on AUC. Coadministration of rifampicin with vicriviroc is not recommended.

Carbamazepine had no effect on vicriviroc when administered with ritonavir (100 mg twice daily). In the presence of ritonavir, addition of another CYP3A4 inhibitor or modestly potent CYP3A4 inducer will not require dose adjustment of vicriviroc. If carbamazepine or rifabutin are coadministered with vicriviroc in a RTV-boosted PI-containing regimen, no vicriviroc dose adjustment is required, but ritonavir should be increased to 100 mg twice daily or 200 mg once daily.

Ref: Kasserra C et al. Assessment of pharmacokinetic and safety interactions between vicriviroc and CYP3A4 substrates, inhibitors, and inducers. Abstract H-230.

Opiate substitution therapy and antiretrovirals

Three studies provided information on the interactions between opiate substitution therapy and ARVs.

The effect of darunavir/r (600/100 mg twice daily for 7 days) on the pharmacokinetics of buprenorphine was assessed in 17 HIVnegative subjects stable on buprenorphine/naloxone maintenance therapy (daily doses up to 24/6 mg). There was no effect on buprenorphine AUC, Cmax or trough concentrations; however, norbuprenorphine Cmax increased by 36% and AUC increased by 46%. No subject required dose adjustment of buprenorphine/naloxone. Given the increase in norbuprenorphine concentrations, close clinical monitoring of patients is recommended. [1]

The effect of raltegravir (400 mg twice daily) on the pharmacokinetics of methadone were investigated in 12 HIV-negative subjects stable on methadone. This study reported that there was no change in either methadone AUC or Cmax in the presence of raltegravir and no dose adjustment is required. [2]

The interaction between buprenorphine and ddI, 3TC and tenofovir was investigated in 27 HIV-negative, buprenorphine/naloxone maintained subjects. Data for ddI and tenofovir were compared to values obtained from 20 control subjects not receiving buprenorphine; 3TC was compared to control data. No significant changes in buprenorphine pharmacokinetics were observed when coadministered with ddI, 3TC and tenofovir. When compared to controls, buprenorphine had no statistically significant effect on NRTI concentrations. [3]

References 1. Sekar VJ et al. Pharmacokinetic (PK) Interaction between darunavir in combination with low-dose ritonavir (DRV/r) and buprenorphine/naloxone (bup/nlx). Abstract H-232. 2. Anderson MS et al. Effect of raltegravir (RAL) on the pharmacokinetics (PK) of methadone. Abstract A1-1295. 3. Baker K et al. Interactions between buprenorphine and antiretrovirals: nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine, lamivudine and tenofovir. Abstract A1-1306.

Darunavir and food

The oral bioavailability and steady state pharmacokinetics of a paediatric oral suspension of darunavir were assessed in two studies in 23 HIV-negative adult subjects. Firstly, ritonavir (100 mg twice daily) was administered on days 1-5 and a single 600 mg dose of darunavir on day 3 as a) tablet with food, b) suspension fasted, and c) suspension with food. In the second part, darunavir pharmacokinetics were assessed following administration of the suspension (600 mg twice daily) with ritonavir (100 mg twice daily) for 7 days. In the first study the criteria for bioequivalence (90% CI of LSM ratios within limits of 80-125%) were met for Cmax and AUC when comparing tablet (with food) and suspension (with or without food).

Pharmacokinetic data obtained with the suspension in the second study were comparable to historical data obtained with the same dose in the tablet formulation. The oral suspension will be further evaluated in paediatric HIV-positive subjects.

Ref: Sekar VJ et al. Bioavailability and food effect of darunavir (DRV) following administration of an oral suspension. Abstract H-233.

Raltegavir and rifabutin

Coadministration of raltegravir (400 mg twice daily) and rifabutin (300 mg once daily) was investigated in 16 HIV-negative subjects. Raltegravir AUC increased by 19%, Cmax increased by 39% and Ctrough decreased by 20%. These changes were not deemed to be clinically significant and no dose adjustment is required.

Ref: Brainard DM et al. Lack of a Clinically important effect of rifabutin (RFB) on raltegravir (RAL) pharmacokinetics. Abstract A1-1296.

Raltegavir and fosamprenavir or fosamprenavir/ritonavir

The interaction between raltegravir and atazanavir or atazanavir/ritonavir and the effect of food was studied in HIV-negative subjects. Raltegravir (400 mg twice daily) and fosamprenavir (1400 mg twice daily) or fosamprenavir/ritonavir (700/100 mg twice daily or 1400/100 mg once daily) were administered alone and in combination with and without a light meal. The effects are summarised in Table 1 below.

Table 1. PK interactions of fosamprenavir doses with raltegravir

Although raltegravir exposure decreased with fosamprenavir, especially at higher doses of ritonavir, raltegravir Cmin were 3- to 9.4-fold higher than the IC95 for WT HIV (14.6 ng/ml). Amprenavir concentrations were decreased, however, Cmins for the boosted regimens were 2.1- to 7.8-fold higher than the EC90 for PI-naive HIV+ patients (228 ng/ml). The clinical implications of these results have yet to be determined.

Ref: Luber A et al. Steady-state pharmacokinetics (PK) of fosamprenavir (FPV) and raltegravir (RAL) alone and combined with unboosted and ritonavir-boosted FPV Abstract A1-1297.

Etravirine and lopinavir/r

This study looked at the interaction between etravirine (200 mg twice daily) and the tablet formulation of lopinavir/ritonavir (400/100 mg twice daily) in 16 HIV-negative subjects. Coadministration decreased etravirine AUC, Cmax and Cmin by 35%, 30% and 45%, respectively; lopinavir AUC, Cmax and Cmin decreased by 13%, 11% and 20%, respectively. There was no change in the pharmacokinetics of ritonavir. These etravirine results are in contrast to previous data obtained with capsule formulation of lopinavir/ritonavir which showed increased etravirine exposure. No dose adjustment of etravirine is required as the effect of lopinavir/ritonavir tablets is similar to the effect of darunavir/ritonavir seen in clinical trials which demonstrated favourable etravirine efficacy and safety. The decrease in lopinavir concentrations was similar to earlier data and is not considered clinically relevant.

Ref: Scholler-Gyure M et al. Pharmacokinetic (PK) Interaction between etravirine (ETR) and lopinavir/ritonavir (LPV/r). Abstract A1-1298.

Etravirine and fluconazole or voriconazole

The pharmacokinetic interaction between etravirine (200 mg twice daily) and fluconazole (200 mg once daily) or voriconazole (200 mg twice daily) was studied in HIV-negative subjects. Fluconazole increased etravirine AUC, Cmax and Cmin by 86%, 75% and 2.09-fold, respectively (n=16); fluconazole AUC, Cmax and Cmin decreased by 6%, 8% and 9%, respectively (n=15). Voriconazole increased etravirine AUC, Cmax and Cmin by 36%, 26% and 52%, respectively (n=16); voriconazole AUC and Cmin increased by 14% and 23%, but Cmax decreased by 5% (n=14). Combinations were generally safe and well tolerated.

Ref: Scholler-Gyure M et al. Pharmacokinetic (PK) interaction between etravirine (ETR) and fluconazole (FLU) or voriconazole (VOR) in HIV negative volunteers. Abstract A1-1299.

LPV/r and echinacea

The effect of echinacea (500 mg three times daily for two weeks) on the pharmacokinetics of lopinavir/ritonavir (400/100 mg twice daily) was studied in 16 HIV-negative subjects. Neither lopinavir nor ritonavir pharmacokinetics were altered by coadministration of echinacea (lopinavir AUC decrease by 4% and there was no change in Cmax). Although echinacea has been shown modulate P450 3A4 in vitro, these data suggest a clinically significant interaction is unlikely.

Ref: Malati CY et al. Echinacea purpurea does not alter the steady state pharmacokinetics of lopinavir or ritonavir in healthy human volunteers. Abstract A1-1307.

“Quad” fixed-dose combination and food

A “quad” fixed dose combination tablet containing emtricitabine (200 mg), tenofovir (300 mg), elvitegravir (150 mg) and the boosting agent GS-9350 (150 mg) is currently in development. This evaluated the effects no food, or light (373 kcal, 20% fat) or high (800 kcal, 50% fat) meals on single doses of the “quad” tablet in 24 HIV? subjects. The pharmacokinetics of emtricitabine were equivalent when given fasted or with either meal. Compared to the fasting state, tenofovir AUC increased by 24% with a light meal and by 23% with a high fat meal; Cmax increase by 20% with a light meal, but was similar to fasting with a high fat meal.

Elvitegravir AUC and Cmax increased by 34% and 22% with a light meal and increased by 87% and 56% with a high fat meal (all compared to fasting). The AUC of GS-9350 was similar with a light meal, but decreased by 17% with a high fat meal (all compared to fasting).

Ref: German P et al. Effect of food on pharmacokinetics (PK) of elvitegravir (EVG), emtricitabine (FTC), tenofovir DF (TDF) and the pharmacoenhancer GS-9350 as a fixed dose combination tablet. Abstract A1-1300.

GS-9350 or ritonavir to boost atazanavir

GS-9350 is CYP3A4 inhibitor currently in development as an alternative boosting agent to ritonavir. The study compared the effects of GS-9350 (100 or 150 mg once daily) and ritonavir (100 mg once daily) on the pharmacokinetics of atazanavir (300 mg once daily) in 33 HIV-negative subjects. The higher dose of GS-9350 was found to be bioequivalent (80-125%) to 100 mg ritonavir (atazanavir GMRs of 1.01 for AUC, 0.92 for Cmax and 0.98 for Cmin). Atazanavir exposure was lower with the lower dose of GS-9350.

Ref: Ramanathan S et al. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir. Abstract A1-1301.

NVP extended release formulation

Nevirapine is licensed for twice daily administration, but is frequently given once daily. Two extended release formulation of nevirapine are currently in development. Patients who were stable on twice daily nevirapine were switch to one of two extended release formulations (XR25% and XR20%). In the 92 patients treated with XR, absorption was decreased – Tmax increased from <2h with the twice daily dosing to 6.7-8.6 h with the XR formulations. Cmin of XR formulations were comparable to the twice daily formulation, whereas Cmax of the XR formulations were lower. Relative bioavailability (based on AUC0-24) was 80% for the XR25% formulation and 71% for the XR20% formulation. No virological failures were observed. The XR25% formulation has been selected for further development due to its increased bioavailability and decreased variability compared to XR20%.

Ref: Quinson A et al. Steady state evaluation of two extended release (XR) nevirapine (NVP) tablets 400 mg QD compared with immediate release (IR) NVP tablets 200 mg BID in HIV-1 infected patients. Abstract A1-1310.