Pratapa Prasad

Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia

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.

Pharmacokinetics of nateglinide in renally impaired diabetic patients.

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.

Pharmacokinetics, Pharmacodynamics, and Safety of Microencapsulated Octreotide Acetate in Healthy Subjects

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 (IM). Concentrations of octreotide, growth hormone (GH), insulin‐like growth factor binding protein 3 (IGFBP‐3), and insulin‐like growth factor 1 (1GF‐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) before day 112. The plateau height (Cplateau (2‐112d, 60%)) was 1.68 ± 0.88 ng/ml, and the duration (Δplateau, 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 IM dose of microencapsulated octreotide acetate was well tolerated in this population.

The effect of valsartan on the angiotensin II pressor response in healthy normotensive male subjects.

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.

Effect of Renal Function on the Pharmacokinetics of Valsartan

SummaryThe 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.Scatter plots of pharmacokinetic parameters did not indicate any clear relationship with creatinine clearance. The regression coefficients of linear, quadratic and cubic terms for the AUC and Cmax of valsartan versus renal function were not significantly different from zero. Thus, the pharmacokinetics of valsartan did not correlate with renal function. In addition, no clinically significant adverse experiences were observed in this trial; the 80mg dose of valsartan was well tolerated. Based on these observations, there is no rationale for dosage adjustment of valsartan in patients with impaired renal function.

Effect of clopidogrel on the steady-state pharmacokinetics of fluvastatin.

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 Cmax 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.

Pharmacokinetics of multiple doses of valsartan in patients with heart failure.

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 ≤ 40% received each dosing regimen starting with the 40-mg dose. On day 7 of each dosing period, serial blood samples were obtained over 12 h for pharmacokinetic assessment. Results showed that the mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased in a linear and nearly proportional manner with valsartan dose. A dose-proportionality assessment, based on a statistical power model, showed that doubling the dose increased the AUC and Cmax 1.8 times. The pharmacokinetics of valsartan are predictable in heart failure patients within the dose range of 40–160 mg BID. Age did not appear to have influenced the valsartan clearance in heart failure patients. The pharmacokinetic values were higher in heart failure patients than in healthy volunteers. All doses were generally safe and well tolerated.

Evaluation of a pharmacokinetic interaction between valsartan and simvastatin in healthy subjects

ABSTRACT Objective: 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 β‑hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period. Results: The results were interpreted based on the point estimates and the 90% confidence intervals.italic> These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC(0–24)) of valsartan, simvastatin β‑hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (Cmax) of valsartan and simvastatin β‑hydroxy acid was increased by 10% and 22%, respectively, and the Cmax of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated. Conclusions: 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 Cmax of valsartan, simvastatin β‑hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.

Pharmacokinetics and pharmacodynamics of the DPP‐4 inhibitor, LAF237, in patients with type 2 diabetes

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).

Assessment of ethnic differences in the pharmacokinetics of valsartan

To assess the ethnic differences in the pharmacokinetics and pharmacodynamics of valsartan between Japanese and Caucasian subjects.