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1.
Int J Clin Pharmacol Ther ; 51(9): 725-37, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23924679

ABSTRACT

OBJECTIVES: Three studies were conducted to assess the pharmacokinetics, methods of administration and ease of swallowability of etravirine tablets. METHODS: Two randomized studies in healthy adults investigated the single-dose pharmacokinetics of etravirine in various dosage strengths and the effects of dispersion in water and film-coating. A third study explored swallowability of etravirine 200-mg tablets in HIV-infected patients. First study: 37 volunteers received 1 × 100-mg non-coated tablet (reference), 4 × 25-mg noncoated tablets and 1 × 100-mg non-coated tablet dispersed in 100 ml water. Second study: 24 volunteers received 2 × 100-mg non-coated tablets (reference), 2 × 100-mg coated tablets, 1 × 200-mg non-coated and 1 × 200-mg coated tablet. Pharmacokinetic parameters were determined using non-compartmental analysis and least square means (LSM) ratios and 90% confidence intervals (CI) were calculated. Third study: 49 virologically-suppressed patients already on an etravirine-containing regimen rated the swallowability of two etravirine formulations (200-mg non-coated and 200-mg coated tablets). RESULTS: In the first study LSM ratios (90% CI) for the etravirine area under the plasma concentration-time curve (AUC) administered either as 4 × 25-mg tablets or 100-mg tablet dispersed were: 0.91 (0.85 to 0.98) and 0.97 (0.90 to 1.03), respectively. In the second study, when comparing a 200-mg non-coated and coated tablet to 2 × 100-mg non-coated tablets, LSM ratios for etravirine AUC were 98 to 99%. In the third study, more patients rated the 200-mg than the 100-mg tablets as acceptable to swallow (70% vs. 43%). CONCLUSIONS: Comparable etravirine exposures were observed regardless of formulation or method of administration (i.e., dispersion); 200-mg tablets were rated as easier to swallow than 100-mg tablets.


Subject(s)
Pyridazines/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Adult , Aged , Biological Availability , Chemistry, Pharmaceutical , Child , Deglutition , Female , Humans , Male , Middle Aged , Nitriles , Pyridazines/adverse effects , Pyrimidines , Tablets
2.
Antimicrob Agents Chemother ; 54(10): 4440-5, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20660678

ABSTRACT

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(τ)]) 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.


Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Rifabutin/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Darunavir , Female , HIV Protease Inhibitors/adverse effects , Humans , Male , Middle Aged , Rifabutin/adverse effects , Ritonavir/adverse effects , Sulfonamides/adverse effects , Young Adult
3.
Clin Ther ; 32(2): 328-37, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20206790

ABSTRACT

BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against both wild-type HIV and viruses harboring NNRTI resistance. Etravirine is mainly eliminated via the hepatobiliary route. OBJECTIVES: This study in HIV- patients with mild or moderate hepatic impairment and healthy matched controls was conducted to explore the effects of mild and moderate hepatic impairment on the steady-state pharmacokinetics of etravirine and to provide guidance for the treatment of HIV+ patients with hepatic impairment. METHODS: This open-label, multiple-dose study enrolled HIV- patients aged 18 to 65 years with mild or moderate hepatic impairment (Child-Pugh score, 5-6 or 7-9, respectively) and healthy volunteers matched for age, sex, race, and body mass index (BMI). All subjects received etravirine 200 mg BID with food for 7 days and a morning dose on day 8. Etravirine pharmacokinetics over a period of 12 hours on days 1 and 8 were determined using noncompartmental methods and analyzed using linear mixed-effects modeling. Tolerability of etravirine was assessed based on the reported adverse events, laboratory investigations, ECG, and physical examination. RESULTS: Each group comprised 8 subjects (mild hepatic impairment patients: 5 men, 3 women; median age, 57 years [range, 41-65 years]; BMI, 26 kg/m(2) [range, 20-32 kg/m(2)]; moderate hepatic impairment patients: 6 men, 2 women; age, 54 years [range, 44-64 years]; BMI, 26 kg/m(2) [range, 22-32 kg/m(2)]). All patients were white and light smokers. On day 8, the least squares mean ratios (90% CIs) of the log transformed pharmacokinetic properties in patients with mild and moderate hepatic impairment were, respectively: C(min), 0.87 (0.65-1.17) and 0.98 (0.68-1.42) microg/mL; C(max), 0.79 (0.63-1.00) and 0.72 (0.54-0.96) ug/mL; and AUC(0-12), 0.87 (0.69-1.09) and 0.82 (0.60-1.11) microg/mL/h. All treatment-emergent adverse events were considered mild to moderate; the most common were headache (50% in healthy controls) and fatigue and nausea (both 25% in patients with mild hepatic impairment). No clinically significant changes in laboratory parameters, physical examination including vital signs, or ECG were observed. One serious adverse event was reported during the follow-up period in a patient with moderate hepatic impairment due to hepatic cirrhosis secondary to alcoholism. This patient presented at screening with dilated cardiomyopathy and cardiac arrhythmia. CONCLUSIONS: In this Phase I pharmacokinetic study, no clinically relevant differences were observed between patients with mild or moderate hepatic impairment and healthy matched subjects with regard to the pharmacokinetics of etravirine. Based on these findings in these HIV- volunteers, no dose adjustment of etravirine appears to be necessary in patients with mild or moderate hepatic impairment. Etravirine was generally well tolerated.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Liver Diseases/metabolism , Pyridazines/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Administration, Oral , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Female , Germany , Humans , Linear Models , Liver Diseases/physiopathology , Male , Middle Aged , Nitriles , Pyridazines/administration & dosage , Pyridazines/adverse effects , Pyrimidines , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/adverse effects , Severity of Illness Index
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