A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.

Rivoceranib (known in China as apatinib) is a selective vascular endothelial growth factor receptor‐2 (VEGFR‐2) tyrosine kinase inhibitor which inhibits angiogenesis in solid tumors. The aim of study was to evaluate potential pharmacokinetic (PK) differences between the Caucasian, Japanese, and Chinese populations. An open‐label, single‐dose, parallel‐design PK study of rivoceranib was conducted in Caucasian, Japanese, and Chinese subjects. A total of 18 healthy males were recruited to each group (54 total), and 201 mg rivoceranib tablets (as 250 mg rivoceranib mesylate) were administered orally to subjects. Plasma samples were collected, and rivoceranib plasma concentration was determined using LC‐MS/MS. For PK analysis, non‐compartmental and compartmental analyses were performed. Intrinsic factors (CYP2C19 and CYP3A4 genotype) were also examined. Non‐compartmental analysis showed no significant difference in AUC0–t, AUC0–∞, Cmax, tmax, and t1⁄2. Apparent clearance and volume of distribution were different across the three populations; however, the extent of this difference does not require dose modification. For compartmental modeling, a two‐compartment model was used to fit the plasma concentrations. No significant difference was observed in absorption, elimination, and intercompartmental transfer rate constants among the three groups. The present study shows no major ethnic PK differences between Caucasian, Japanese, and Chinese populations.

Treatment of Alzheimer's disease sometimes uses combinations of drugs because dementia is frequently associated with behavioral symptoms. Risperidone and donepezil are both metabolized through cytochrome P450 2D6 and 3A4, raising the possibility of drug interactions with combination therapy. The objective of this study was to determine whether significant drug interactions occur with concomitant administration of donepezil and risperidone. In an open-label, three-way crossover study, 24 healthy men were randomly assigned to receive 0.5 mg of risperidone twice daily, 5 mg of donepezil once daily, or both drugs for 14 consecutive days, followed by a 21-day washout period. The treatment ratios of AUC and associated 90% confidence intervals (CIs) for risperidone active moiety, defined as risperidone plus 9-hydroxyrisperidone (ratio = 110.2%; 90% CI = 103.7-117.2), and for donepezil (ratio = 97.1%; 90% CI = 90.0-103.6) were within the 80% to 125% of bioequivalence range. The treatment ratios of Cmax and associated 90% CIs for risperidone active moiety (ratio = 114.6%; 90% CI = 107.0-122.8) and for donepezil (ratio = 96.1%; 90% CI = 90.0-102.6) were also within the bioequivalence range. Therefore, no significant pharmacokinetic differences occurred in either risperidone active moiety or donepezil when given alone or in combination. Adverse events (predominantly headache, nervousness, and somnolence) were minor and comparable for all treatment groups. The results indicate that no clinically meaningful drug interactions occurred between risperidone 1 mg daily and donepezil 5 mg daily at steady state, and therefore no dosage adjustment is required when both drugs are combined with the dosage regimen studied. Additional investigations are warranted to determine the potential for interactions in elderly patients with dementia who may eliminate risperidone and donepezil more slowly and thus be more vulnerable to clinical drug interactions than the young healthy subjects examined in this study.

Cisapride can be administered safely to patients receiving low therapeutic dosages of fluoxetine.

This randomized, open-label, comparative study assessed the pharmacokinetics and safety of intravenous and oral hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions of itraconazole in patients with advanced human immunodeficiency virus (HIV) infection. All patients received 1-hour intravenous infusions of itraconazole 200 mg twice dailyfor 2 days, then once dailyfor 5 days. Patients were then randomized to receive itraconazole oral solution, 200 mg twice daily or 200 mg once daily, for a further 28 days. Itraconazole was solubilized by HP-beta-CD in both intravenous and oral solutions, so HP-beta-CD concentration in plasma was measured. Thirty-two patients were enrolled and analyzed (n = 32 for intravenous treatment, 32 completed; n = 16 for oral once daily, 15 completed; n = 16 for oral twice daily, 12 completed). Steady-state plasma concentrations of itraconazole and hydroxyitraconazole were reached by days 3 and 6, respectively. After intravenous dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were 906 ng/ml and 1,690 ng/ml, respectively. During oral dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were maintained or increased in the 200 mg twice-dailygroup but fell with the 200 mg once-daily oral dose. Itraconazole was generally well tolerated and had a favorable safetyprofile; minor changes in hematology variables were noted during the intravenous phase, and HP-beta-CD was cleared rapidly, mostly in urine. Twenty-eight patients (88%) experienced at least one adverse event; no adverse event was severe, and only seven were definitely related to itraconazole. In conclusion, itraconazole 200 mg given intravenously twice daily for 2 days, then once daily for 5 days, rapidly achieves amean steady-state trough concentration of itraconazole of over 250 ng/ml, which is associated with clinic outcome and is effectively maintained with itraconazole oral solution 200 mg twice daily in patients with advanced HIV infection.