ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects

The absolute oral bioavailability and pharmacokinetics of clindamycin administered to 16 healthy volunteers and 16 patients with AIDS were compared. Clindamycin was given intravenously (i.v.) (Cleocin phosphate) at a dose of 600 mg as a 25-min infusion and orally (Cleocin hydrochloride) by use of a crossover design in both study groups. Plasma samples were analyzed by gas-liquid chromatography. Plasma drug clearance and volume of distribution at the steady state following the i.v. dose differed between study groups. The clearances were 0.27 0.06 liter/h/kg in healthy volunteers and 0.21 0.06 liter/h/kg in AIDS patients (P = 0.014; Mann-Whitney U test); the volumes of distribution at the steady state were 0.79 + 0.13 and 0.66 0.12 liter/kg in healthy volunteers and AIDS patients, respectively (P = 0.005). The elimination half-life did not differ between the two groups. The bioavailability of clindamycin capsules in AIDS patients was approximately 1.5 times that in healthy volunteers (0.53 + 0.14 versus 0.75 + 0.20; P = 0.002). Peak concentrations following the oral dose were higher in AIDS patients as well (7.7 2.5 versus 5.3 1.0 mg/liter, P = 0.0008). Three AIDS patients experienced severe diarrhea following the oral dose; four patients had mild diarrhea following the i.v. dose. No adverse effects were reported by the healthy volunteers. The pharmacokinetic parameters observed in this study for AIDS patients may be useful for the consideration of clindamycin dosage regimens in patients treated for toxoplasmic encephalitis. These findings suggest that the effect of AIDS on drug disposition deserves further investigation, particulariy for orally administered drugs.Toxoplasmic encephalitis (TE) is considered the most common cause of intracerebral mass lesions in patients with AIDS, occurring in 3 to 40% of AIDS patients (16). Standard therapy for TE includes the synergistic combination of pyrimethamine and sulfadiazine, which provides a sequential blockade of folic acid metabolism. However, many patients with AIDS are unable to complete a course of therapy because of adverse reactions (18).Clindamycin has been used either alone or more frequently in combination with pyrimethamine to treat TE in patients with AIDS who develop untoward side effects to the sulfonamide component of the standard pyrimethaminesulfadiazine therapy (4,10,15,21,23,24). Recently, the results of an international prospective study comparing the combinations pyrimethamine-sulfadiazine and pyrimethamine-clindamycin suggest that the relative efficacies of the two combination treatments are approximately equal (3).The activity of clindamycin against Toxoplasma gondii is controversial: clindamycin was effective in a murine model of TE (11) but was ineffective in a model based on Taxoplasma-infected rat monocytes (9). Clindamycin does not penetrate adequately into cerebrospinal fluid, even in the presence of bacterial meningitis (7); however, it has been suggested that damage of the blood-brain barrier in AIDS patients, involving marked tissue de...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS• This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIMVismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of 14 C-vismodegib with single and multiple oral doses. METHODSHealthy post menopausal female subjects (n = 6/group) received either a single or daily 150 mg vismodegib oral dose with a 14 C-labelled 10 mg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for 14 C-vismodegib by accelerator mass spectrometry. RESULTSFollowing a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h -1 , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h -1 and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSIONVismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.

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Tipranavir (TPV), a novel nonpeptidic protease inhibitor (NPPI), was administered to treatment-naive HIV-1-infected patients over 14 days in a randomized, multicenter, open-label, parallel-group trial to evaluate the efficacy and tolerability of a self-emulsifying drug delivery system (SEDDS) formulation, in combination with ritonavir (RTV). Of the 31 patients enrolled, 10 were randomized to receive TPV 1200 mg twice daily (TPV 1200), 10 patients received TPV 300 mg + RTV 200 mg twice daily (TPV/r 300/200), and 11 patients received TPV 1200 mg + RTV 200 mg twice daily (TPV/r 1200/200). The median baseline viral load and CD4 cell count were 4.96 log10 copies/mL and 244 cells/mm, respectively. After 14 days, the median decrease in viral load was -0.77 log10 in the TPV 1200 group, -1.43 log10 in the TPV/r 300/200 group, and -1.64 log10 in the TPV/r 1200/200 group. TPV exposure was increased by 24- and 70-fold in the TPV/r 300/200 and 1200/200 groups, respectively, compared with TPV 1200 alone. There were no significant differences across treatment arms with regard to drug-related adverse events. TPV/r appeared to be safe, effective, and well tolerated during 14 days of treatment.

The findings of this study indicate that rifampin induces the metabolism of delavirdine. Therefore therapy with rifampin is contraindicated in patients receiving delavirdine mesylate.

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Clindamycin, which is usually used in combination with pyrimethamine, has been proven effective in the treatment of cerebral toxoplasmosis in human immunodeficiency virus-infected patients. However, it is not known if clindamycin achieves inhibitory concentrations at the site of infection. Also, it has been hypothesized that the activity of clindamycin against Toxoplasma gondiimay be due, at least in part, to a metabolite. We evaluated the penetration of clindamycin and its major metabolite,N-demethylclindamycin (NDC), into cerebrospinal fluid (CSF) of AIDS patients undergoing lumbar puncture for diagnostic purposes. A single, 1,200-mg dose of clindamycin was administered as a 45-min intravenous infusion beginning at 1.5 or 2.5 h before CSF sampling. The concentrations of clindamycin in CSF ranged from 0.091 to 0.429 mg/liter at 1.5 h and from 0.120 to 0.283 mg/liter at 2.5 h following the beginning of the infusion. The concentrations of clindamycin in CSF were well above the 50% inhibitory concentration of 0.001 mg/liter and the parasiticidal concentration of 0.006 mg/liter. NDC was undetectable both in plasma and in CSF. Our study provides a pharmacokinetic rationale for the clinical efficacy of clindamycin in the treatment of cerebral toxoplasmosis.