Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects

Ford, Susan L.; Chen, Ya-Chi; Lou, Yu; Borland, Julie; Min, Sherene; Yuen, Geoffrey J.; Shelton, Mark J.

doi:10.1128/aac.00724-07

Cited by 27 publications

(28 citation statements)

References 9 publications

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“…Previous drug-drug interaction studies between DTG and protease inhibitors have reported no clinically significant alteration in the PK of TPV, atazanavir, darunavir, and lopinavir (4-6). The PK parameters of APV observed in the current study were similar to those presented in previously published data (16,17). Therefore, the results from the current study are consistent with the lack of a significant effect of DTG on the CYP450 enzymes involved in the metabolism of protease inhibitors.…”

Section: Discussionsupporting

confidence: 81%

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Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

Song

Borland

Chen

et al. 2014

Antimicrob Agents Chemother

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objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established "no-effect" boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier NCT01209065.) T he integrase inhibitor (INI) class of antiretroviral drugs has proven to be a valuable addition to treatment strategies for the management of HIV. Good tolerability and lack of cross-resistance to other classes of antiretroviral therapy have contributed to the use of INIs in the antiretroviral regimen for both treatmentexperienced and treatment-naive patients (1). Dolutegravir (DTG) is an unboosted, once-daily [QD] INI that can be differentiated from previous INIs (e.g., raltegravir [RAL] and elvitegravir) by its resistance profile and predictable pharmacokinetics (PK) with low to moderate intersubject variability (2, 3). Drugdrug interaction studies between ritonavir (RTV)-boosted protease inhibitors (i.e., tipranavir [TPV], darunavir, lopinavir, and atazanavir) and DTG have been conducted previously to evaluate changes in the plasma exposure to DTG. These studies have reported modest changes in DTG PK, and dosage adjustments are not required when administered with most commonly used RTVboosted protease inhibitors, except for TPV-RTV (4-6).Dolutegravir is metabolized primarily via uridine 5=-diphosphoglucuronosyltransferase-1A1 (UGT1A1), although cytochrome P450 3A4 (CYP3A4) has a minor role (10% to 15%) in the process, and it is a substrate of the transport protein P-glycoprotein (7,8). Therefore, drugs that induce or inhibit these metabolic pathways may affect the plasma exposure of DTG. Dolutegravir does not in...

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Section: Discussionsupporting

confidence: 81%

“…Table 4 lists the mean steady-state plasma PK of APV following coadministration of DTG and FPV-RTV. Amprenavir exposure following coadministration of DTG and FPV-RTV was similar to historical data, suggesting that DTG does not affect APV exposure (16,17).…”

Section: Resultssupporting

confidence: 58%

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

Song

Borland

Chen

et al. 2014

Antimicrob Agents Chemother

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“…Other studies have also reported an increased AE profile when RFB and boosted PIs are coadministered in healthy volunteers (7,15,28). Similar findings were observed in another study of healthy volunteers receiving a boosted PI and rifampin (3), where the incidence of liver-related AEs was higher than seen in HIV-1-infected patients in routine clinical management.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the overall safety profile for DRV/r, no dose adjustment of DRV is considered necessary. Given the safety profile seen with concomitant RFB (150 mg QOD) and a boosted PI in healthy volunteers in this and other studies (7,15,28), it is not recommended to conduct further studies with this combination in healthy volunteers. …”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

Sekar¹,

Lavreys²,

Casteele³

et al. 2010

Antimicrob Agents Chemother

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The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC 12h ) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (C min ) increased by 64% and the maximum plasma concentration (C max ) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUC ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n ‫؍‬ 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.The protease inhibitor (PI) darunavir (DRV) with low-dose ritonavir (DRV/r) has demonstrated substantial efficacy and safety across the whole treatment spectrum of HIV-1-infected patients (6,13,14). DRV/r is approved in the United States (25), Europe (26), and other countries for treatment-experienced (600/100 mg twice a day [BID]) and treatment-naïve (800/100 mg once a day [QD]) HIV-1-infected adult patients.Rifabutin (RFB) is an antibiotic used in patients with HIV infection to prevent and treat disseminated Mycobacterium avium complex infections and (in combination with other agents) to treat tuberculosis (16). Patients already receiving DRV/r may, therefore, also need to receive RFB.The predominant metabolite of RFB is 25-O-desacetylrifabutin (desRFB), which is normally present at 10-fold lower plasma concentrations than RFB. DesRFB has similar activity to RFB and contributes up to 10% o...

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HIV–TB Drug Interactions

Oni

Pepper

Wilkinson

2009

AIDS and Tuberculosis

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Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects

Cited by 27 publications

References 9 publications

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

HIV–TB Drug Interactions

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