First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses < or =2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.

Clinical-pharmacological strategies to assess drug interaction potential during drug development.

Drug interactions in patients receiving multiple drug regimens are a constant concern for the clinician. With the increased availability of new drugs and their concomitant use with other drugs, there has been a rise in the potential for adverse drug interactions as demonstrated by the recent withdrawals of newly marketed drugs because of unacceptable interaction profiles. Therefore, the interaction potential of a new compound has to be assessed in detail, starting with preclinical in vitro and in vivo studies at candidate selection and continuously followed up through preclinical and clinical development. Since formal in vivo studies of all possible drug interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated in vivo during the development phase is indicated. Based on knowledge of pharmacokinetic and biopharmaceutical properties, a well balanced link between in vitro investigations and carefully selected in vivo interaction studies allows full assessment of the potential of a new drug to cause clinically relevant pharmacokinetic drug-drug interactions, prediction of a lack of interactions and derivation of the proper dose recommendations. Clinical pharmacology plays a number of key roles within the process of collecting information on drug interactions during preclinical and clinical development: addressing issues and/or favourable properties to be expected, thus contributing to the scientific assessment of development potential; setting up a rational in vivo drug-drug interaction programme; performing early mechanistic studies to link in vitro with in vivo information (employing 'cocktail' approaches if possible); reviewing co-medication sections for clinical trials; and conducting labelling-oriented interaction studies, after proof of concept. The fact that interactions can occur between various active substances should by itself be a conclusive argument against unnecessary polypharmacy. Prescribing fewer drugs on a rational basis can reduce the risk of adverse effects secondary to drug interactions and may help to improve the quality of drug treatment and to save costs.

The pharmacokinetics of cerivastatin in patients on chronic hemodialysis.

OBJECTIVE: The single-dose and steady-state pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin and its two major metabolites, M-1 and M-23, were evaluated in patients with renal failure on chronic hemodialysis. METHODS: After having given their informed consent, 12 end-stage renal disease patients (5 female/7 male; 18 to 63 years) received a single-dose of 0.2 mg cerivastatin sodium followed by a 4-hour dialysis session for pharmacokinetic profiling. Two to four weeks later, all patients received 0.2 mg once-daily as maintenance treatment for a period of 7 days during which PK profiling was carried out on Days 1 and 7/8, both being dialysis-free days. Plasma concentrations of parent drug and active metabolites were measured by HPLC with fluorescence detection. In addition, assessment of lipid parameters, safety and tolerability, and a complete clinical chemistry program were included in the study procedures. RESULTS: Cerivastatin was well-tolerated and no serious adverse events were observed. In spite of the short treatment period, treatment responses with respect to total cholesterol, LDL cholesterol and triglycerides lowering were observed. Mean cerivastatin and metabolite concentrations and thus systemic exposure were slightly higher (up to 50%) in patients on chronic dialysis compared to previous studies carried out in healthy subjects. The unbound fraction of cerivastatin ranged from 0.6 - 1.5% in these patients (normal range: 0.5 - 0.9%). The half-lives of both parent drug (approximately 3 h) and metabolites remained unaffected and, most notably, no accumulation occurred under repeated dosing. In addition, cerivastatin clearance was not increased by concurrent dialysis as would be predicted from the high plasma protein-binding (> 99%), and there were no significant differences in cerivastatin exposure between the dialysis period and the dialysis-free profile days. CONCLUSION: Cerivastatin can be safely administered in the usual dosages to patients with end-stage renal disease on chronic hemodialysis. Based on the observed moderate increase in cerivastatin mean exposure, patients should be started at the lower end of the recommended dosing range and subsequent titration should be performed with caution.

Clinical pharmacokinetics of cerivastatin.

Cerivastatin sodium, a novel statin, is a synthetic, enantiomerically pure, pyridine derivative that effectively reduces serum cholesterol levels at microgram doses. Cerivastatin is readily and completely absorbed from the gastrointestinal tract, with plasma concentrations reaching a peak 2 to 3 hours postadministration followed by a monoexponential decay with an elimination half-life (t1/2beta) of 2 to 3 hours. Cerivastatin pharmacokinetics are linear: maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) are proportional to the dose over the range of 0.05 to 0.8 mg. No accumulation is observed on repeated administration. Cerivastatin interindividual variability is described by coefficients of variation of approximately 30 to 40% for its primary pharmacokinetic parameters AUC, Cmax and t1/2beta. The mean absolute oral bioavailability of cerivastatin is 60% because of presystemic first-pass effects. Its pharmacokinetics are not influenced by concomitant administration of food nor by the time of day at which the dose is given. Age, gender, ethnicity and concurrent disease also have no clinically significant effects. Cerivastatin is highly bound to plasma proteins (>99%). The volume of distribution at steady state of about 0.3 L/kg indicates that the drug penetrates only moderately into tissue; conversely, preclinical studies have shown a high affinity for liver tissue, the target site of action. Cerivastatin is exclusively cleared via metabolism. No unchanged drug is excreted. Cerivastatin is subject to 2 main oxidative biotransformation reactions: demethylation of the benzylic methyl ether moiety leading to the metabolite M-1 [catalysed by cytochrome P450 (CYP) 2C8 and CYP3A4] and stereoselective hydroxylation of one methyl group of the 6-isopropyl substituent leading to the metabolite M-23 (catalysed by CYP2C8). The product of the combined biotransformation reactions is a secondary minor metabolite, M-24, not detectable in plasma. All 3 metabolites are active inhibitors of hydroxymethylglutaryl-coenzyme A reductase with a similar potency to the parent drug. Approximately 70% of the administered dose is excreted as metabolites in the faeces, and 30% in the urine. Metabolism by 2 distinct CYP isoforms renders cerivastatin relatively resistant to interactions arising from inhibition of CYP. If one of the pathways is blocked, cerivastatin can be effectively metabolised by the alternative route. In addition, on the basis of in vitro investigations, there is no evidence for either cerivastatin or its metabolites having any inducing or inhibitory activity on CYP. The apparent lack of any clinically relevant interactions with a variety of drugs commonly used by patients in the target population supports this favourable drug-drug interaction profile.

Pharmacokinetics of cerivastatin when administered under fasted and fed conditions in the morning or evening.

OBJECTIVE: The influence of food and time of drug dosing on the pharmacokinetics of cerivastatin, a potent HMG-CoA reductase inhibitor, was evaluated in 24 healthy male subjects between 21 and 44 years of age. METHODS: A single-dose, four-way crossover design was employed, with each subject receiving cerivastatin 0.8 mg at weekly intervals under each of four conditions: 8 a.m. dosing after an overnight fast (reference), 8 a.m. dosing with a high-fat breakfast (test), 6 p.m. dosing with the evening meal (low-fat; test), and 10 p.m. dosing 4 h after dinner (reference). Plasma concentrations of the parent compound and its active metabolites were measured by high performance liquid chromatography with fluorescence detection subsequent to post-column derivatization. RESULTS: The calculated 90% confidence intervals for cerivastatin AUC and Cmax were completely contained within the range 0.8 to 1.25. Thus, no relevant influence of food could be detected, although the presence of food increased the Cmax of cerivastatin on average by 12% (90% confidence interval: 1.04 - 1.21) under morning, but not evening dosing. With respect to the effect of daytime on cerivastatin pharmacokinetics, AUCs were bioequivalent for all treatment conditions, with Cmax values slightly lower (8 - 19%) following evening dosing, irrespective of food intake. Cerivastatin was well tolerated by the subjects in the study. CONCLUSION: Food effect bioequivalence according to current guidelines could be demonstrated. Cerivastatin can be administered independent of meal intake at dinner or at bedtime, the preferred time of dosing for statins because the rate of hepatic cholesterol synthesis is greatest at night.

Quantitative analysis of pharmacokinetic study samples by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).

The basis of all pharmacokinetic evaluations are powerful assays to quantify drugs and/or metabolites in biological matrices using modern sensitive instrumental analytical techniques, such as capillary gas chromatography and high-performance liquid chromatography (HPLC). Being both specific and universal, mass spectrometry (MS) is an ideal chromatographic detector. Due to recent exciting achievements in the interfacing of liquid chromatography (LC) and MS, LC-MS, like the successfully preceding hyphenated technique gas chromatography-mass spectrometry (GC-MS), has now become a valuable technique in the analyst's toolbox. The key features of LC-MS are explained and four examples demonstrating its potential for highly specific and sensitive routine drug assays with the option of high sample throughput in pharmacokinetic investigations are presented.

Biopharmaceutical profile of cerivastatin: a novel HMG-CoA reductase inhibitor.

The biopharmaceutical properties of cerivastatin were evaluated in a series of worldwide clinico-pharmacological studies. Young healthy males aged 18-45 years were randomized to receive 0.05-0.8 mg cerivastatin orally, given either as single or multiple once-daily doses under fed or fasting conditions in the morning, with evening meal or at bedtime. Following administration, cerivastatin was rapidly and almost completely absorbed into the gastrointestinal tract (> 98%), with maximum plasma concentrations (Cmax) reached at 2-3 h post dose. The plasma concentration/time profile of the tablet is similar to an aqueous oral solution (relative bioavailability is 100%). The dose-proportionality of cerivastatin (0.05-0.8 mg) in area under the curve and Cmax showed low intra- and interindividual variability. The effect of food (single-dose studies testing administration of cerivastatin with a high-fat meal and clinical investigations in patients) or time of administration (single- and multiple-dose once-daily/twice-daily studies) had no clinically relevant effects on the pharmacokinetics of cerivastatin. Marketed tablet strengths and drug formulations from different sources were found to be bioequivalent. Cerivastatin is a noncomplicated drug with respect to its biopharmaceutical profile and bioavailability.

Pharmacokinetic variability of nimodipine disposition after single and multiple oral dosing to hypertensive renal failure patients: parametric and nonparametric population analysis.

OBJECTIVES: To explore the contribution of renal failure to nimodipine overall pharmacokinetic variability after single and multiple oral dosing and to develop a population pharmacokinetic model by means of the nonparametric expectation maximization (NPEM2) algorithm based on sampled individual drug concentrations close to the estimated patients' C(SS)avs (NPEM2-C(SS)av). PATIENTS, MATERIALS AND METHODS: 24 hypertensive patients with normal and reduced renal function, without clinical and laboratory data for hepatic dysfunction, were enrolled in the study and their nimodipine plasma levels were analyzed by means of a parametric and nonparametric population pharmacokinetic modeling using a maximum a posteriori Bayesian (MAPB) estimator in an iterative two-stage Bayesian population modeling program and NPEM2-algorithm. RESULTS: Comparison of parameter dispersion revealed higher variability of nimodipine disposition after the first dose than at steady-state except for apparent volume of distribution at steady-state, V(SS)/F, whose variability increased from 98% to 223%. The most variable was mean residence time, MRT, whose coefficient of variation (CV) was 288% after the first dose and decreased by more than 2 times at steady-state, followed by terminal elimination half-life, t(1/2el), with CV = 171% after the first dosing and decreasing by more than 3 times at steady-state. Concerning the impact of renal failure on disposition parameters variability, patients with slightly to moderately reduced renal function, creatinine clearances between 51 to 80 and 25 to 50 ml/min, resp., stated higher variation than patients with more definitively altered renal function. The validation of NPEM2-C(SS)av population model was performed by using a set of 272 individual plasma drug concentrations, including trough levels as well as concentrations belonging to mono-exponential elimination phases after single and multiple dosing. Bayesian forecasting, using 4 trough levels per patient as Bayesian priors, revealed highly significant correlation between observed and population model predicted drug concentrations (r = 0.526, p < 0.0001). The predictive performance of NPEM2-C(SS)av population model was characterized by low bias (mean error = -0.48 microg/l, 95% CI = -0.99-0.04 microg/l), and good precision (root mean squared error = 4.32 microg/l, 95% CI = -2.53-11.17 microg/l). CONCLUSIONS: As predicted for high hepatic clearance drugs [Rowland 1985], nimodipine parameters variability decreased after reaching steady-state. NPEM2-C(SS)av population model demonstrated high accuracy and precision in predicting drug levels from terminal exponential phase including trough levels at steady-state.

Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients.

OBJECTIVE: The mutual drug-drug interaction potential of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use. METHODS: Plasma and urine concentrations of cerivastatin and its major metabolites were determined after administration of 0.2 mg single-dose cerivastatin to 12 kidney transplant recipients (9 men and 3 women) who were receiving stable individual cyclosporine treatment (mainly 200 mg twice a day). These results were compared with the single-dose pharmacokinetic results obtained from a healthy control group (n = 12, age-comparable men). Cerivastatin steady-state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day treatment of 0.2 mg cerivastatin once a day. Cyclosporine steady-state concentration-time profiles were determined in blood with monoclonal (EMIT [enzyme multiplied immunoassay technique] assay, parent drug specific) and polyclonal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclosporine plus metabolites) during cerivastatin cotreatment and compared with predosing data. RESULTS: Coadministration of 0.2 mg cerivastatin once a day to the kidney transplant recipients treated with individual doses of cyclosporine and other immunosuppressive agents resulted in a 3- to 5-fold increase in cerivastatin and metabolites plasma concentrations. Cerivastatin and metabolites elimination half-lives were unaffected, and no accumulation occurred during multiple-dosing conditions. Cerivastatin had no influence on steady-state blood concentrations of cyclosporine or cyclosporine metabolites in these patients. The concomitant use of both drugs was well tolerated. CONCLUSIONS: Cerivastatin and metabolites plasma concentrations were significantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for cerivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes may explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites.

Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance.

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.

The effect of omeprazole pre- and cotreatment on cerivastatin absorption and metabolism in man.

OBJECTIVE: Cerivastatin, a novel HMG-CoA reductase inhibitor, is exclusively cleared via cytochrome P450-mediated biotransformation and subsequent biliary and renal excretion of the metabolites. The presented study was performed to determine the influence of the gastric acid secretion inhibitor omeprazole on bioavailability and pharmacokinetics of cerivastatin. METHOD: In a controlled, randomized, non-blind two-way crossover study single oral doses of 0.3 mg cerivastatin were administered in 12 healthy male subjects under fasting conditions either alone or together with 20 mg omeprazole following a 4-day pretreatment with oral 20 mg omeprazole once daily. RESULTS: The mean AUC and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.00 (0.92 - 1.09) and 0.94 (0.80 - 1.16) for cerivastatin. Similar results were obtained for the metabolites of cerivastatin and for omeprazole. CONCLUSION: No metabolic inhibitory interaction was noted for either cerivastatin or its major active metabolites, nor for omeprazole, respectively. In addition, the change in gastric pH as consequence of the inhibition of gastric acid secretion exerted by omeprazole had no influence on cerivastatin absorption.

Lack of drug-drug interaction between cerivastatin and nifedipine.

Cerivastatin is a novel, potent HMG-CoA reductase inhibitor. It is primarily cleared via demethylation and hydroxylation with involvement of cytochrome P450 (CYP) 3A4 and subsequent biliary and renal excretion of the metabolites. Both cerivastatin and the dihydropyridine calcium antagonist nifedipine, which is primarily metabolized by CYP 3A4, are used concomitantly in the prevention and therapy of coronary heart disease. To study the drug-drug interaction potential, the mutual effects of cerivastatin and nifedipine were investigated in a controlled, randomized, non-blind 3-way crossover study in healthy male subjects. Single oral doses of 0.3 mg cerivastatin or of 60 mg nifedipine were administered either alone or concomitantly under fasting conditions. The mean AUC- and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.04 (0.98 - 1.10) and 1.00 (0.93 - 1.07) for cerivastatin, and 0.98 (0.73 - 1.32) and 0.95 (0.80 - 1. 13) for nifedipine, respectively. Our results indicate that no mutual drug-drug interaction between cerivastatin and nifedipine occurs.

Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions.

Pharmacokinetic drug-drug interactions influence drug efficacy, tolerability, and compliance. Such interactions are both more common and of more clinical relevance than often appreciated. The US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have recently issued guidelines setting out in vitro and in vivo investigations to be conducted during drug development. These guidelines reflect the increasing interest of public health authorities in this topic. Cerivastatin is a novel, potent HMG-CoA reductase inhibitor that effectively reduces serum cholesterol levels at low daily doses. It is completely absorbed after oral administration, undergoes moderate first-pass metabolism and high plasma protein binding, and is cleared exclusively via hepatic cytochrome P450 (CYP). Unlike other drugs of its class, cerivastatin has a dual metabolic pathway, with the involvement of more than one CYP isozyme. Metabolites are cleared via both biliary and renal excretion. On the basis of this pharmacokinetic profile and a knowledge of the target population, the formal in vivo interaction programme for cerivastatin investigated many important potential cerivastatin drug-drug interactions. Cerivastatin appears to lack clinically relevant interactions with digoxin, warfarin, antacid, cimetidine, nifedipine, omeprazole, erythromycin and itraconazole.

Inter-ethnic comparisons of the pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.

AIMS: During the world-wide clinical development of the HMG-CoA reductase inhibitor cerivastatin, pharmacokinetic data have been collected from studies performed in Europe, North America and Japan, covering different ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to search for any inter-ethnic differences in cerivastatin pharmacokinetics. METHODS: All concentration data were assessed by fully validated specific h.p.l.c. assays employing post-column photochemical derivatization with ultra-violet light and subsequent fluorescence detection. The comparability of analytical results was guaranteed by cross-validations between all analytical laboratories. The inter-ethnic comparison was based on retrospective analysis of the overall pharmacokinetic data pool (n = 340 complete profiles) in the key parameters AUC, Cmax, tmax and t1/2, assessed via non-compartmental methods. RESULTS: Based on the comparison of selected individual single- and multiple-dose escalation studies in healthy young males, performed when starting the clinical development, exposure and disposition of the parent compound and its cytochrome P450-mediated biotransformation products M-1 and M-23, and amounts of metabolites M-1, M-23 and M-24 excreted in urine were comparable for US Americans, mainly Caucasians, and Japanese. Retrospective analysis of the complete pharmacokinetic data pool revealed that there are no statistically significant differences in dose-normalized AUC- and Cmax-values. The respective ratios of weight-adjusted geometric least-squares (LS) means (95% confidence intervals) between Japanese and Caucasians were: for AUCdose-norm 0.96 (0.86-1.08) for single dose, and 1.04 (0.86-1.24) for multiple dose; for Cmax,dose-norm 0.93 (0.83-1.05) for single dose, and 1.01 (0.82-1.25) for multiple dose. Half-life was slightly, but statistically significantly shorter in Japanese than in Caucasian subjects following single dose: ratios (95% CI) were 0.68 (0.61-0.77) for single dose, and 1.00 (0.79-1.26) for multiple dose. Times to peak tended to be slightly greater in Japanese: differences of weight-adjusted LS means (95% CI) were 0.60 h (0.28 h-0.92 h) for single dose, and 1.15 h (0.48 h-1.81 h) for multiple dose. Black and Hispanics did not differ in their pharmacokinetic characteristics from Caucasians. CONCLUSIONS: Based on inter-study comparisons and a retrospective analysis of the complete PK data pool there is no evidence for any clinically relevant inter-ethnic differences in cerivastatin pharmacokinetics in Caucasians, Black and Japanese subjects after oral therapeutic doses.

Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.

OBJECTIVE: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydroxylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. METHODS: Twelve healthy young male subjects received single oral doses of 300 microg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays. RESULTS: Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (Cmax) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective Cmax results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). CONCLUSIONS: Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 microg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin.

Grapefruit juice increases oral nimodipine bioavailability.

The bioavailability of dihydropyridine calcium channel blockers following oral administration was shown to be increased by concomitant intake of grapefruit juice for all drugs of this class tested up to now. Here we report a randomized crossover interaction study on the effects of grapefruit juice on the pharmacokinetics of nimodipine and its metabolites. Eight healthy young men (4 smokers/4 nonsmokers) were included. Nimodipine was given as a single 30 mg tablet (Nimotop) with either 250 ml of water or 250 ml of grapefruit juice (751 mg naringin/l). Drug concentrations in plasma withdrawn up to 24 hours postdose were measured by GC-ECD, and model-independent pharmacokinetic parameters were estimated. The study was handled as an equivalence problem. Point estimators and ANOVA based 90% confidence intervals (CI) were calculated for the test (= grapefruit juice period) to reference (= water period) ratios using dose-normalized concentrations. The absence of a relevant interaction was assumed if the CIs were within the 0.67-1.50 range. Cmax for nimodipine reached 124% of the reference period (90% CI 0.76-2.01), AUC was increased to 151% (90% CI 114%-200%), respectively. The null hypothesis "relevant interaction" thus could not be rejected for the primary pharmacokinetic parameters AUC and Cmax. The ratios of metabolite AUC to parent drug AUC were slightly reduced with grapefruit juice intake. Additionally, there was evidence for a more pronounced hemodynamic response in the grapefruit juice period. To avoid the interaction, nimodipine should not be taken with grapefruit juice.

Influence of cholestyramine on the pharmacokinetics of cerivastatin.

The possible influence of the bile acid sequestering agent cholestyramine, a basic comedication in hypercholesterolemic patients, on the pharmacokinetics of the new HMG-CoA reductase inhibitor cerivastatin was investigated. When both drugs were administered concomitantly in the morning under fasting conditions, a decrease in relative bioavailability by 21% could be observed, possibly due to irreversible adsorption of the statin to the resin. In addition, the delay in absorption led to a 41% decrease in cerivastatin mean maximum plasma concentration which also occurred at later time. A second study addressed in detail the question of time interval required between both treatments to minimize the influence of cholestyramine pretreatment on cerivastatin bioavailability: dosing of cerivastatin at dinner (6 p.m.) or bed time (10 p.m.) with cholestyramine pretreatment 1 hour before meal (5 p.m.) in both treatments. The decrease in mean AUC was now approximately 8-16% depending on the time of pretreatment (1-hour-interval: 16%, 5-hour-interval: 8%), and Cmax decreased by approximately 32%, irrespective of the time of pretreatment. Tmax was increased in both treatments, whereas t1/2 was not changed. The presented data support the conclusion that when administered concomitantly, the bioavailability of cerivastatin is moderately reduced by adsorption to cholestyramine. Following, however, the dosing instructions of both cholestyramine (1 hour before meal) and cerivastatin (once-daily in the evening at dinner or at bed time), i.e. administering both drugs several hours (at least 1 hour) apart, the observed effects on rate and extent of absorption of cerivastatin are unlikely to be of clinical relevance.

Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin.

To determine the absolute bioavailability of the HMG-CoA reductase inhibitor cerivastatin, 12 healthy young male volunteers received single doses of either 100 micrograms as a 1-minute bolus infusion or 200 micrograms orally as tablets in a controlled, randomized crossover study. In addition, 8 of the 12 subjects participated in a third treatment period in which 200 micrograms cerivastatin were administered as an oral solution as reference for determining the relative bioavailability of the tablet drug formulation. Plasma samples were analyzed for cerivastatin by a specific HPLC assay with fluorescence detection after post-column irradiation of the eluate, with a limit of quantification of 0.1 microgram/l. Following all treatments, cerivastatin was well tolerated and no clinically relevant adverse events or changes in laboratory parameters were observed. Vital signs and ECG remained unchanged. Plasma concentration/time profiles of cerivastatin following intravenous bolus could be described by a 2-compartment model with a distribution half-life of 3-5 min and an elimination half-life of 1.5-2.4 h. For the 2 oral administrations a 1-compartmental pharmacokinetic model with a first-order absorption process was best to describe the plasma concentration/time data. Based on the AUCnorm values of the 7 subjects, valid for complete pharmacokinetic evaluation, the absolute bioavailability of tablet and oral solution was 60.0 and 59.6% (90% confidence intervals 53-68%), respectively. The relative bioavailability of tablet compared with solution was 100.7% (90% confidence interval 89-114%), with tablet and oral solution showing nearly identical in vivo absorption characteristics and almost superimposable plasma concentration/time curves. The tablet formulation, therefore, can be regarded as an optimal oral formulation with respect to galenic aspects.