Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration–time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

An open-label study was conducted of nelfinavir mesylate, given with reverse transcriptase inhibitors to human immunodeficiency virus 1 (HIV-1)-infected infants and children 3 months to 13 years of age. Doses of nelfinavir mesylate of 20-30 mg/kg yielded drug exposures comparable to those seen in adults. The drug was well tolerated; mild diarrhea was the primary toxic effect observed. Seventy-one percent (39) of the 55 evaluable subjects had an initial decrease in plasma HIV-1 RNA, of at least 0.7 log10 copies/mL; suppression of plasma HIV-1 RNA levels to < 400 copies/mL was observed in 15. Children who began taking at least one new reverse transcriptase inhibitor near the time when nelfinavir mesylate was started, and those with a > or = 24% proportion of CD4 lymphocytes, had a greater chance of achieving and maintaining a decline in plasma HIV-1 RNA to < 400 copies/mL. Suppression of viremia was achieved in children as young as 3 months of age.

Background and ObjectivesLesinurad is a selective uric acid reabsorption inhibitor (SURI) under investigation for the treatment of gout. This study elucidated the interaction of lesinurad with major liver and kidney transporters in vitro and evaluated the drug–drug interactions (DDIs) of lesinurad and atorvastatin, metformin, and furosemide in clinical studies.MethodsLesinurad interaction with membrane transporters was evaluated in validated transporter-expressing cell systems and analyzed by liquid scintillation counting. Healthy male subjects (ages 18–65 years; body mass index 18–32 kg/m2) received atorvastatin (40 mg; n = 28) with or without lesinurad 200 or 400 mg, or received metformin (850 mg; n = 12) or furosemide (40 mg; n = 11) with or without lesinurad 400 mg. Plasma concentrations of each concomitant drug were determined by validated liquid chromatography with tandem mass spectrometry methods.ResultsLesinurad interacted in vitro with OATP1B1, OCT1, and OAT1/3 transporters. Co-administration of lesinurad 200 mg did not significantly alter plasma exposure (maximum concentration [Cmax] and area under the concentration–time curve [AUC]) of total atorvastatin (atorvastatin + hydroxyl-metabolites) or atorvastatin, while co-administration of lesinurad 400 mg increased the Cmax of total atorvastatin and atorvastatin by 17–26 %, but had no effect on AUC. Co-administration of lesinurad 400 mg had no effect on the plasma exposure of metformin. Furosemide plasma AUC was reduced by 31 % in the presence of lesinurad 400 mg, but furosemide renal clearance and diuretic activity were unchanged.ConclusionsNo clinically relevant DDIs were observed between lesinurad and substrates of major liver or kidney transporters.

To test the hypothesis that the cytochrome P-450-inhibiting antiepileptic drug (AED) stiripentol (STP) can reduce the incidence of phenytoin (PHT) induced congenital malformations, we chronically administered the AEDs to three inbred mouse strains. The frequency of congenital defects in PHT-treated animals was dosage dependent, ranging from 7 to 55%. When STP was coadministered orally with PHT, there was a significant reduction in fetal defects in SWV and C57BL/6J mouse strains. A replication of the experiment was conducted with addition of a seventh group of mice that received the high dosage of PHT together with STP. In the replicate, all three strains demonstrated a significant reduction in fetal defects in fetuses exposed to PHT (60 mg/kg) and STP (200 mg/kg) as compared with PHT (60 mg/kg) monotherapy. These results strongly suggest that oxidative metabolites activated by cytochrome P-450 are the primary teratogenic molecules involved in PHT-induced teratogenesis and that clinical management of pregnant epileptic patients may be improved through heightened awareness of these drug interactions.

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Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4 ؉ cell count of 266 cells/mm 3 . Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that when used in a combination regimen produce marked and durable reductions in HIV-1 RNA levels in treated patients (4, 5, 7). Although protease inhibitors (PIs) are commonly prescribed individually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), the evaluation of regimens with two or more PIs has progressed for several reasons. First, combinations of PIs can have potentially beneficial pharmacokinetic interactions such as higher drug levels (1). Second, these pharmacokinetic interactions allow for less-frequent dose administration and reduced dietary restrictions that may lead to improved adherence (2). Finally, combinations of PIs may have increased potency as a result of complementary resistance profiles and enhanced activity against viral quasispecies.This study describes the results of a multiple-dose (steadystate) analysis that was designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the IDV plus NFV combination given every 12 h (q12h) to HIV-1-infected patients. Although at present dual PIs are usually administered in combination with NRTIs, the present study was conducted at a time when combinations of dual PI therapy...

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