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To evaluate posaconazole pharmacokinetics in subjects with different degrees of hepatic impairment compared with matched healthy subjects.A total of 37 subjects were enrolled in this open-label, single-dose, parallel-group study; 19 with hepatic impairment and 18 healthy subjects with matching demographics. Each subject received a single 400-mg oral dose of posaconazole after a high-fat meal. Blood samples for analysis were taken up to 648 h ( approximately 4 weeks) postdose.Compared with maximum plasma concentration (C(max)) values in matched subjects with normal hepatic function, values were higher among subjects with moderate hepatic impairment (517 vs. 724 ng/mL) but lower among subjects with severe hepatic impairment (608 vs. 403 ng/mL). No clear trend toward increased or decreased exposure was observed with increasingly severe hepatic impairment, and extensive overlap occurred between normal and hepatically impaired subjects. Therefore, pharmacokinetic variables C(max) and area under the curve from time 0 to the time of final quantifiable sample (AUC(tf)) values were pooled for subjects with hepatic impairment. Pooled C(max) values were similar to the pooled normal groups (607 vs. 605 ng/mL), whereas there was an overall 36% increase in exposure (AUC(tf)) for the pooled hepatic impairment group compared with the pooled normal group. Posaconazole was well-tolerated, with six (33%) healthy subjects and six (32%) hepatically impaired subjects reporting adverse events.The data from this small single-dose study suggest posaconazole is safe. Furthermore, although limited by the small number of subjects enrolled, the authors feel that dose adjustments are probably not necessary in patients with hepatic impairment; however, physicians should continue to monitor posaconazole use in patients with hepatic impairment.

To investigate the potential for a pharmacokinetic interaction between fluvastatin modified-release 80mg tablet (Lescol((R)) XL; fluvastatin XL) and amlodipine 5mg tablet (Norvasc((R))) following multiple once-a-day doses for 2 weeks.This was a single-centre, six-sequence, three-period, randomised, crossover design study. Fluvastatin XL 80mg tablet and amlodipine 5mg tablet were administered once a day for 2 weeks either alone or in combination. Fluvastatin and amlodipine serum concentration profiles were characterised on day 14 for each treatment. The pharmacokinetic interaction between the two drugs was evaluated based on the p-values and 90% confidence intervals (CIs) for log-transformed highest observed concentration (C(max)), area under the plasma concentration-time curve calculated by the linear trapezoidal method up to 24 hours (AUC(24)), and apparent oral clearance at steady state (CL/F), using a single entity as the reference treatment and the combination as the test treatment. Adverse events (AEs), safety laboratory tests and physical examinations were evaluated for safety.Twenty-four healthy subjects were enrolled and 19 completed the study. The safety analysis was based on data from all 24 subjects who received at least one dose of a treatment, while the pharmacokinetic analysis was based on data from the 19 subjects who completed all treatments.The coadministration of fluvastatin XL and amlodipine resulted in no significant changes in the steady-state AUC (469 vs 454 mug . h/L), C(max) (96 vs 89 mug/L), and CL/F (197 vs 232 L/h) of fluvastatin when compared with fluvastatin XL alone. The p-values for these comparisons were between 0.172 and 0.238, and the 90% CIs for the geometric means were within 78% and 139%. A similar comparison for amlodipine showed no significant difference in the steady-state AUC (132 vs 140 mug . h/L), C(max) (7.1 vs 7.5 mug/L) and CL/F (41 vs 40 L/h) of amlodipine. The p-values for these comparisons were between 0.309 and 0.353, and the 90% CIs for the geometric means were within 90% and 111%. The majority of the AEs were mild in severity. There were no clinically relevant changes in clinical laboratory results, physical examinations or vital sign parameters.There were no significant differences in the steady-state pharmacokinetics of fluvastatin or amlodipine when they were administered together and the small differences observed were not clinically relevant. Therefore, no dose adjustment of either drug is necessary when fluvastatin and amlodipine are coadministered.

The potential for a drug interaction was investigated between nateglinide, an oral antidiabetic agent, and acenocoumarol, an oral anticoagulant, as these drugs are primarily metabolized via CYP2C9.A two-period, randomized, double-blind, two-way crossover study design was employed to evaluate the effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol in 11 healthy male or female subjects. All subjects received either nateglinide 120 mg t.i.d. or placebo for 5 days in a crossover fashion and a single 10-mg dose of acenocoumarol on day 3. Plasma concentrations of R- and S-acenocoumarol and the anticoagulation parameters [prothrombin time (PT) and international normalized ratio of PT (PTINR)] were determined for 72 h following acenocoumarol administration. The pharmacokinetic and pharmacodynamic parameters of acenocoumarol were determined by noncompartmental analysis.The mean (coefficient of variation (CV%)) area under the concentration-time curve (AUC(0-t)) of R-acenocoumarol in the presence and absence of nateglinide was 4217 (23%) and 3831 (24%) ng.h/ml, respectively. The corresponding values for S-acenocoumarol were 397 (20%) and 382 (23%), respectively. The mean (CV%) C(max) of R-acenocoumarol in the presence and absence of nateglinide was 304 (16%) and 316 (16%), respectively and the corresponding values for S-acenocoumarol were 142 (36%) and 141 (34%), respectively. The 90% confidence intervals indicated that exposure parameters, AUC(0-t) and C(max), of both R- and S-acenocoumarol were within the acceptable limits of 0.8-1.25. The mean (CV%) of area under the concentration-time curve of PT (AUC(PT)) following acenocoumarol administration in the presence and absence of nateglinide was 1170 (10%) and 1136 (8%), respectively. The corresponding AUC(INR) values were 104 (13%) and 99 (10%), respectively. Nateglinide co-administration has no influence on the PT or PTINR of acenocoumarol (p0.05).Co-administration of nateglinide does not influence either the pharmacokinetics or the anticoagulant activity of R- and S-acenocoumarol in healthy subjects. This suggests that no dosage adjustments will be required when nateglinide and acenocoumarol are coadministered in clinical practice.

Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open-label, single-dose, two-center study included patients (mean age = 57 +/- 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age-, sex-, height-, and weight-matched healthy controls (n = 20). All participants received a single 120-mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmax or AUC0-t between the groups. Nateglinide was eliminated rapidly in all groups (t1/2 = 1.9-2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired.

Fluvastatin sodium (Lescol, Novartis Pharmaceutical Corp., East Hanover, NJ, U.S.A.), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor that limits cholesterol biosynthesis, is available as a 40-mg immediate-release formulation capsule. An extended-release formulation for once-daily administration has been developed for patients with primary hypercholesterolemia who may benefit from doses higher than 40 mg/day. This phase I study evaluated the safety, tolerability, and pharmacokinetics of a new fluvastatin extended-release formulation at doses ranging from 80-640 mg/day in 40 hypercholesterolemic patients. After a 2-week dietary stabilization phase, patients (Fredrickson type IIa/IIb), 18-55 years of age, were randomly assigned to four groups to receive oral fluvastatin extended-release (80, 160, 320, or 640 mg) or matching placebo once daily for 13 days. Fluvastatin extended-release was generally safe and well tolerated at doses of 80-320 mg/day. Within this dose range, linear pharmacokinetics was observed after single and multiple dosing. At 640 mg, fluvastatin extended-release was not well tolerated. Six of the seven actively treated patients at this dose experienced adverse events, including diarrhea, headache, and clinically relevant elevations in serum transaminase concentrations. In addition, nonlinear pharmacokinetics, possibly due to saturation of first-pass metabolism, was observed at this dose, causing higher than expected serum drug concentrations. Once-daily administration of fluvastatin extended-release at doses of 80-320 mg/day was generally safe and well tolerated in patients with primary hypercholesterolemia over a 13-day dosing period.

The effect of renal function on the pharmacokinetics of valsartan was investigated in this trial. In order to cover the full spectrum of renal function, a total of 19 subjects with normal renal function and various degrees of renal dysfunction, as determined by creatinine clearance (CLCR), were assigned to four groups: normal renal function (CLCR > 90 ml/min), and mild (CLCR 61 to 90 ml/min), moderate (CLCR 30 to 60 ml/min) and severe (CLCR < 30 ml/min) renal dysfunction. Creatinine clearance was determined following a 24-hour urine collection just prior to drug administration. Each subject received a single oral dose of 80mg of valsartan (capsule) after an overnight fast. Blood samples were collected at frequent intervals up to 48 hours postdose and plasma valsartan concentrations were determined. Pharmacokinetic parameters [area under the plasma concentration-time curve (AUC), maximum plasma valsartan concentration (Cmax), time to reach Cmax (tmax), and the terminal elimination half-life (t½)] were calculated. Statistical analysis using a cubic polynomial regression function was performed to examine a relationship between renal function and the pharmacokinetic parameters of valsartan.

The aim of the study is to determine the effect of posaconazole , an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin.This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 - 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 - 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 - 13).Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the C(max) and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC).These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

Pharmacokinetic data from a randomized, parallel-group, multicenter study are presented. Adults with toenail onychomycosis ( n = 146) received posaconazole (100 mg, 200 mg, or 400 mg) once daily (QD) for 24 weeks or 400 mg QD for 12 weeks. The posaconazole concentration in the great toenail exhibited a dose-related increase starting at week 2 for 24 weeks and a mean toenail-to-plasma concentration ratio of approximately 3:1 at the end of treatment for the 400-mg 24-week dose.

This study assessed the effects of clopidogrel, a CYP 2C9 inhibitor, on fluvastatin pharmacokinetics in healthy volunteers. The effects of combined clopidogrel-fluvastatin treatment on platelet function were also determined. Subjects received 80 mg fluvastatin (extended-release formulation) alone on days 1 through 9, 80 mg fluvastatin and 300 mg clopidogrel (loading dose) on day 10, and 80 mg fluvastatin and 75 mg clopidogrel (maintenance dose) on days 11 through 19. Compared to treatment with fluvastatin alone, fluvastatin AUC was similar and C(max) increased marginally (15.7%) with concomitant treatment with clopidogrel. Platelet aggregation was inhibited by clopidogrel by 33% two hours after the loading dose and by 47% at steady state, similar to that reported for clopidogrel alone treatment. The authors conclude that coadministration of fluvastatin and clopidogrel has no clinically relevant effect on fluvastatin pharmacokinetics or on platelet inhibition by clopidogrel.

The potential for a pharmacokinetic drug interaction between valsartan, an antihypertensive drug, and simvastatin, a lipid-lowering agent, was investigated in this study. This was an open-label, multiple-dose, randomized, three-period, cross over study in 18 healthy subjects. Each subject received one 160 mg valsartan tablet or one 40 mg simvastatin tablet or co-administration of valsartan (160 mg) and simvastatin (40 mg) tablets for 7 days, with a 7-day inter-dose washout period. The steady-state pharmacokinetics of valsartan, simvastatin beta-hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period.The results were interpreted based on the point estimates and the 90% confidence intervals. These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC(0-24)) of valsartan, simvastatin beta-hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (C(max)) of valsartan and simvastatin beta-hydroxy acid was increased by 10% and 22%, respectively, and the C(max) of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated.Based on the wide therapeutic dosage ranges of valsartan and simvastatin, and the highly variable pharmacokinetics of three analytes, the observed differences in the exposure and C(max) of valsartan, simvastatin beta-hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.

The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (approximately 70%) metabolized via CYP2C9.This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method.The administration of nateglinide in combination with sulfinpyrazone resulted in approximately 28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20-1.39) with no differences in mean peak plasma concentration (Cmax; 90% CI test-reference ratio: 0.86-1.12) compared with nateglinide-alone treatment. The time to reach Cmax (tmax) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated.Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.

This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days).

Angiotensin II has adverse actions in heart failure including vasoconstriction, aldosterone secretion, and activation of the sympathetic nervous system. Valsartan, a potent specific angiotensin II type 1 receptor blocker, may produce beneficial effects in heart failure. The purpose of this study was to evaluate the steady-state pharmacokinetics of valsartan 40, 80, and 160 mg each given every 12 h for 7 days in heart failure patients. Eighteen patients with chronic stable heart failure and left ventricular ejection fractions

The pharmacokinetics, pharmacodynamics, and safety of the marketed formulation of microencapsulated octreotide acetate were evaluated in an open-label study in 22 healthy cholecystectomized subjects. Each subject received a single 30 mg dose of microencapsulated octreotide acetate intramuscularly (i.m.). Concentrations of octreotide, growth hormone (GH), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin-like growth factor 1 (IGF-1) as well as clinical safety were evaluated over a period of 112 days (16 weeks). After the injection, mean serum octreotide concentration initially increased rapidly, reached the maximum (Cmax, day 1 = 0.96 +/- 0.25 ng/ml) approximately 1.5 hours after dosing, and declined thereafter until 24 hours postdose (Cmin, 24 h = 0.088 +/- 0.093 ng/ml). The octreotide concentration then increased and started a sustained release from day 7 onward. Plateau concentrations were maintained through day 70 and gradually declined to below the lower limit of quantification (LLOQ) by day 112. The plateau height (Cplateau (2-112d, 60%)) was 1.68 +/- 0.88 ng/ml, and the duration (delta plateau, 60%) was 30.2 +/- 15.7 days. The integrated concentration-time curve, AUC0-112d, was 2819 +/- 782 (ng.h/ml), and the apparent half-life (t1/2) was 169 hours. To assess the variability, the drug concentrations were determined hourly for 8 hours on day 28, and the mean octreotide concentration, Cavg, day 28' was 1.55 +/- 1.26 ng/ml. The suppression of IGF-1 was statistically significant compared to the baseline (p < 0.05) through day 63; however, there were no appreciable changes in GH and IGFBP-3 concentrations after a single injection of microencapsulated octreotide acetate. Simulation of a 28-day dose schedule suggested that steady-state octreotide concentrations would be reached by the third injection with steady-state concentrations about twofold greater than the first injection. There were no serious adverse events or clinically meaningful changes in vital signs, ECGs, or laboratory evaluations observed in this study, indicating that the 30 mg i.m. dose of microencapsulated octreotide acetate was well tolerated in this population.

Objective Valsartan is an oral antagonist of angiotensin II that competes with angiotensin II for the AT1-receptor and is being developed as an antihypertensive agent. This study assessed the ability of 80 mg valsartan to inhibit the pressor effect of exogenous angiotensin II in healthy normotensive men, first after a single dose and then after multiple doses once daily for 7 days. Methods This was a single-center, double-blind, placebo-controlled, randomized crossover study. Six healthy men underwent angiotensin II challenges to determine a suitable dose required to increase their systolic blood pressure by approximately 30 mm Hg. Each subject then received an 80 mg dose of valsartan or matching placebo. The inhibition of the angiotensin II pressor effect was determined by the systolic blood pressure response to repeated angiotensin II challenges at multiple time points. Results Systolic blood pressure responses to angiotensin II challenges after single and multiple doses of valsartan were significantly lower than placebo, indicating that valsartan blocked the blood pressure response to angiotensin II. The maximum blocking effect was observed within 2 to 3 hours. Mean data suggested that differences in effect between valsartan and placebo were similar after both single and multiple doses and persisted up to 24 hours after administration. The angiotensin II blocking effect was maintained up to this time, despite low plasma valsartan levels and minimal accumulation after multiple doses. Conclusion Valsartan, 80 mg, is a potent angiotensin II antagonist with a rapid onset of action and persistent angiotensin II inhibition up to 24 hours. There is no attenuation of this effect after multiple doses. Clinical Pharmacology & Therapeutics (1997) 61, 35–44; doi

Background LAF237 is a selective DPP-4 inhibitor under development as an anti-diabetic agents. The objective of this study was to assess the PK/PD in patients with type 2 diabetes (T2D). Methods Thirteen patients were enrolled and 12 completed this study. Each patient was randomly assigned to receive one of the four treatments for 28 days: placebo (PBO), 10, 25, or 100 mg of LAF237 bid. Blood samples were collected on day 28 for measurement of LAF237, DPP-4, GLP-1, glucose and insulin over 16 hr while standard mixed meals were served. Results LAF237 was rapidly absorbed and the Cmax was observed during 1~2 hr. Both Cmax and AUC increased dose proportionally. More than 90% DPP-4 inhibition was achieved after all doses, while the duration of >90% DPP-4 inhibition increased with dose. LAF237 100 mg bid increased GLP-1 levels >2 fold compared to placebo. Mean glucose levels over 14 hr were significantly reduced by 10% and 19%, respectively, at 25 mg and 100 mg bid compared to PBO (p

In this study, the potential for ethnic differences in the pharmacokinetics and pharmacodynamics of valsartan between Japanese and Caucasian subjects was assessed. This was an open-label, parallel design study conducted in age and body weight matched healthy male Japanese (n=15) and Caucasian (n=15) subjects. All subjects received a single oral dose of 160 mg valsartan capsule, and the plasma levels of valsartan, aldosterone, and angiotensin II along with plasma renin activity (PRA) were determined at pre-determined time intervals post-dosing. The time to reach peak plasma concentrations of valsartan (Tmax) was in the range of 1–6 h in both groups. The mean Cmax of valsartan was 3.3 and 3.5 µg/mL in Japanese and Caucasian subjects, respectively, and the corresponding mean plasma exposure (AUC0-∞) values were 23.0 and 23.8 µg.h/mL. The mean elimination half-life (t1/2) of valsartan was 7.7 and 9.6 h in Japanese and Caucasian subjects, respectively. No significant difference (p>0.1) was found between two ethnic groups for PRA, angiotensin II and aldosterone at 2, 4 and 8 h post dose. In conclusion, pharmacokinetics and pharmacodynamics of valsartan were not found to be ethnic sensitive between healthy male Caucasian and Japanese subjects following single oral dose administration of valsartan.