Potential for pharmacokinetic interactions between ambrisentan and cyclosporine.

Ambrisentan (ABS), approved for the treatment of pulmonary arterial hypertension and administered as an oral dose once daily, is an ET(A)-selective endothelin receptor antagonist (ERA) and a potential substrate for cytochrome P450 (CYP) 3A4, organic anion-transporting polypeptide (OATP), and P-glycoprotein (P-gp). Cyclosporin A (CsA), an inhibitor of CYP3A4, P-gp, and OATP, may be used concomitantly with ABS. In this open-label, parallel-treatment study, 28 healthy subjects received steady-state ABS (5 mg q.d.) either alone or with steady-state CsA (100-150 mg b.i.d.), and 24 other subjects received steady-state CsA either alone or with steady-state ABS. In the presence of CsA, ABS maximum plasma concentration (C(max)) increased 1.5-fold, and area under the plasma concentration-time curve (AUC)(0-τ) increased twofold. Marginal increases were observed for CsA C(max) (906 vs. 1,014 ng/ml) and AUC(0-τ) (3.05 vs. 3.37 µg·h/ml) in the presence of ABS. Frequent adverse events (AEs) were headache and gastrointestinal disorders. The addition of ABS to steady-state CsA appeared less tolerable as compared with the addition of CsA to steady-state ABS. A maximum ABS dose of 5 mg is recommended if it is coadministered with CsA. No change in CsA dose is recommended if it is coadministered with ABS.

A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state.

PURPOSE: To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies. METHODS: In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3beta, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance. RESULTS: Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC(0-24) when OSI-461 was administered with food. An increase in pGSK-3beta post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 --> A34 and C421 --> A421, occurred at frequencies of 11.76 and 29%, respectively. CONCLUSIONS: Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents.

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design.

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m2/d x 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m2/d x 5. The recommended Phase II dose i s 4.3mg/m2/d x 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8-8.4 mg/m2/d x 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.

Time-dependent influence of pentoxifylline on the pharmacokinetics of orally administered carbamazepine in human subjects.

The time-dependent influence of pentoxifylline (PTX) on the pharmacokinetics of carbamazepine (CBZ) was studied after single-dose oral administration of 100 mg CBZ either alone or in combination with 400 mg PTX at 10:00 and 22:00 h. Serum samples were collected at predetermined time intervals and analysed for unchanged CBZ using high-performance liquid chromatography. The pharmacokinetic parameters of CBZ were calculated using the model-independent method. PTX reduced the rate (Tmax, 8.58 +/- 2.64 vs 5.66 +/- 1.44 h; K(a); 0.47 +/- 0.14 vs 0.72 +/- 0.19 h(-1)), but not the extent of CBZ absorption at 22:00 h treatment. However, such a change was not observed for 10:00 h treatment. No significant changes were observed in other pharmacokinetic parameters of CBZ under the influence of PTX for both 10:00 h as well as 22:00 h treatments. The clinical significance of the time-dependent influence of PTX on the rate of absorption of CBZ will be revealed upon extension of the study to patients.

Chronopharmacokinetics of sumatriptan in healthy human subjects.

Rhythms in the onset and symptoms of several diseases are well established. Migraine is a disorder that exhibits periodicity in its symptoms and so chronotherapy may be beneficial in treating the problem. Designing a chronotherapeutic schedule requires chronopharmacokinetic and chronopharmacodynamic data of the drugs prescribed. We have studied the chronopharmacokinetics of sumatriptan, a drug of choice in migraine treatment. Twelve healthy male volunteers were treated with 100 mg sumatriptan orally at 0700, 1300, 1900 and 0100 h in a randomized 4 x 4 Latin square crossover design, with a wash-out period of one week. Serum samples were analysed by high performance liquid chromatography with an electrochemical detector. Pharmacokinetic parameters were calculated using noncompartmental methods. The pharmacokinetic parameters were analysed using analysis of variance and a two-tailed paired t-test at the probability of 95%. The mean peak serum concentration following the 0700 h administration (Cmax; 59.09 +/- 10.53 ng mL(-1)) was significantly (P < 0.05; n = 12) higher than after the 1900 h administration (Cmax 41.88 +/- 12.21 ngmL(-1)). The mean area under the serum concentration-time curve from time zero to the last time-point (AUCo-t), the area under the serum concentration-time curve from zero to infinity (AUC 0-infinity), and the area under the first moment curve (AUMC) were significantly (P < 0.05; n = 12) higher following the 0700 and 0100 h administrations than after the 1900 h administration. Following administration at 0700 h, the mean oral clearance (CLs/f; 781 +/- 186 mL h(- 1) kg(-1)) and the apparent volume of distribution (Vd/f; 2,379 +/- 684) were significantly lower (P < 0.05; n = 12) than after the 1900 h administration (CLs/f 1,208 +/- 458 mL h(-1) kg(-1), Vd/f 4,655 +/- 2,096 mL kg(-1)). The mean Vd/f value was again lower after the 1300h administration than after the 1900 h administration (2,763 +/- 1,417 vs 4,655 +/- 2,096 mL kg(-1); P < 0.05; n = 12). The variations may be due to the time dependent changes in the extent of absorption and/or circadian variations in hepatic blood flow.

Correlation of serum and salivary levels of pentoxifylline.

Twelve healthy volunteers were treated with 400 mg pentoxifylline at 1000 and 2200 hours in a randomized crossover design with a washout period of 1 week. Serum and saliva samples were analyzed for unchanged pentoxifylline by high-performance liquid chromatography. Saliva to serum ratios and pharmacokinetic parameters of pentoxifylline were calculated. Significant (p < 0.05) correlation between serum and salivary levels of pentoxifylline was observed for the treatments at 1000 and 2200 hours. Although the mean saliva/serum ratios of pentoxifylline in the postabsorption phase were found to be higher for the 2200-hour treatment than the 1000-hour treatment, this difference was not statistically significant (p > 0.05). Further, no significant (p > 0.05) difference was noted between the mean pharmacokinetic parameters of pentoxifylline whether computed through serum or through salivary levels for either treatment. Hence, saliva can be used in place of serum/plasma in pharmacokinetic and interaction studies of pentoxifylline.