This study compared the bioavailability of two candidate fixed-dose combinations (FDCs: G003 and G004) of darunavir/cobicistat 800/150 mg with that of darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short-term safety and tolerability of the FDC formulations were also assessed. This open-label trial included 36 healthy volunteers and assessed steady-state pharmacokinetics of darunavir over 3 randomized, 10-day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid-chromatography tandem mass-spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng ∙ h/mL and G004: 76,490 ng ∙ h/mL) was comparable to that following darunavir/ritonavir (78,410 ng ∙ h/mL), as was Cmax (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short-term tolerability of the FDCs was comparable to that of darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset, or rash. Cobicistat is an effective pharmacoenhancer of darunavir when administered as an FDC. Short-term administration of darunavir/ritonavir or darunavir/cobicistat was generally well tolerated.
This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.
Total darunavir exposure decreased during pregnancy, but the decrease was less for unbound (active) darunavir. These changes are not considered clinically relevant. Darunavir/ritonavir 800/100 mg qd may therefore be a treatment option for HIV-1-infected pregnant women.
IntroductionPhysiologic changes during pregnancy may impact the pharmacokinetics of drugs. In addition, efficacy and safety/tolerability concerns have been identified for some antiretroviral agents.MethodsHuman immunodeficiency virus (HIV)-1–infected pregnant women (18–26 weeks gestation) receiving the non-nucleoside reverse transcriptase inhibitor rilpivirine 25 mg once daily were enrolled in this phase 3b, open-label study examining the impact of pregnancy on the pharmacokinetics of rilpivirine when it is given in combination with other antiretroviral agents. Blood samples (collected over the 24-h dosing interval) to assess total and unbound rilpivirine plasma concentrations were obtained during the second and third trimesters (24–28 and 34–38 weeks gestation, respectively) and 6–12 weeks postpartum. Pharmacokinetic parameters were derived using noncompartmental analysis and compared (pregnancy versus postpartum) using linear mixed effects modeling. Antiviral and immunologic response and safety were assessed.ResultsNineteen women were enrolled; 15 had evaluable pharmacokinetic results. Total rilpivirine exposure was 29–31% lower during pregnancy versus postpartum; differences were less pronounced for unbound (pharmacodynamically active) rilpivirine. At study entry, 12/19 (63.2%) women were virologically suppressed; 10/12 (83.3%) women were suppressed at the postpartum visit. Twelve infants were born to the 12 women who completed the study (7 discontinued); no perinatal viral transmission was observed among 10 infants with available data. Rilpivirine was generally safe and well tolerated in women and infants exposed in utero.ConclusionDespite decreased rilpivirine exposure during pregnancy, treatment was effective in preventing mother-to-child transmission and suppressing HIV-1 RNA in pregnant women. Results suggest that rilpivirine 25 mg once daily, as part of individualized combination antiretroviral therapy, may be an appropriate option for HIV-1–infected pregnant women.Trial RegistrationClinicalTrials.gov Identifier, NCT00855335.
Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug-drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily.
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