Jochen Kuhlmann

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

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.

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.

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

AbstractObjective: 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; hydro‐xylation 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 μg 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 μg, 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.

When Are Bioavailability Studies Required? A German Proposal

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their “Guidelines on interchangeability of multisource pharmaceutical products.” This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form

AbstractObjective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 μg · l–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l–1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean Cmax of 8.7 μg · l–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min−1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.

Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype.

The metabolism of acetaminophen (paracetamol) is thought to be altered in patients with Gilberts syndrome (GS), a chronic unconjugated hyperbilirubinemia. The underlying cause of GS is a polymorphism in the promotor region of the uridine diphosphate glucuronosyltransferase isoform 1A1 gene (UGT1A1*28), its encoded enzyme being responsible for the glucuronidation of bilirubin and presumably acetaminophen. Decreased enzyme activity results in elevated bilirubin levels and may activate various metabolic pathways leading to higher amounts of potentially hepatotoxic acetaminophen metabolites. Patients with GS might be more susceptible to unexpected side effects while taking acetaminophen and other drugs which are substrates of UGT1A1. The possibility of a correlation between glucuronidation capacity with respect to acetaminophen, UGT1A1 promotor polymorphism and the bilirubin serum level were investigated in 23 healthy male volunteers selected for UGT1A1 genotype (6 wildtypes, 9 mutants and 8 heterozygotes). One gram acetaminophen was administered p.o. and urine was collected over 2 4-hour periods. Unchanged acetaminophen and its glucuronide metabolite were determined using HPLC. The metabolic ratios unchanged acetaminophen/acetaminophen glucuronide in UGT1A1-wildtypes, heterozygotes and mutants showed no statistically significant differences. An association between metabolic ratio and serum bilirubin level could not be detected in any of the urine collection periods. These data confirm that there is no correlation between the capacity to glucuronidate acetaminophen, the UGT1A1 genotype and the bilirubin serum level. Acetaminophen is likely to be substrate of a UGT isoform other than the UGT1A1.

Nimodipine. Potential for drug-drug interactions in the elderly.

Nimodipine is indicated for a variety of conditions in elderly patients. Elderly patients often have multiple morbidity and receive treatment with a variety of drugs. Therefore, it is important to investigate the possible pharmacokinetic and pharmacodynamic interactions of nimodipine with various drugs commonly prescribed for elderly patients. There were no clinically relevant interactions of nimodipine with any of the following specific agents studied: the antiarrhythmics mexiletine, propafenone, disopyramide or quinidine, digoxin, the beta-adrenoceptor antagonists propranolol or atenolol, nifedipine, warfarin, diazepam, indomethacin, ranitidine or glibenclamide (glyburide). However, there were some notable interactions. In epileptic patients taking the anticonvulsants carbamazepine, phenobarbital (phenobarbitone) and/or phenytoin, there was a 7-fold decrease in the area under the plasma concentration versus time curve (AUC) and an 8- to 10-fold decrease in the maximum plasma concentration of nimodipine. These effects were to be expected, considering the hepatic enzyme-inducing properties of these anticonvulsant drugs. Therefore concomitant use of these agents with oral nimodipine is not recommended. In contrast, epileptic patients treated with nimodipine and valproic acid (sodium valproate) showed an increase in both the AUC (approximately 50%) and maximum plasma concentrations (approximately 30%) of nimodipine, which may be explained by valproic acid inhibiting the presystemic oxidative metabolism of nimodipine. Concomitant administration of cimetidine produced an approximate doubling of the bioavailability of nimodipine. This again was to be expected, considering the known inhibitory effect of cimetidine on cytochrome P450. However, no changes in haemodynamics, clinical or laboratory status or tolerability were observed, and dose adjustment did not appear to be clinically necessary.

Guidances related to bioavailability and bioequivalence: European industry perspective

SummaryThe investigations of bioavailability and bioequivalence can be classified according to three separate areas of information. Firstly, estimation of bioavailability judged on a drug substance’s in vivo characteristics taking into account solubility, polymorphism, stability (especially under the conditions of the GI tract), gut wall permeability and first pass metabolism. Secondly, evaluation of formulation properties including dissolution profile in the GI tract and its contribution to exposure variability with respect to the desired absorption characteristics. Finally, maintaining quality during the market phase with respect to equivalence to the clinical trial formulations.While in the first two areas the range of the estimated mean values and the intra- and inter-subject variabilities contain the desired information for proper medical decisions, in the third area the mean values and their confidence limits describe the quality with regard to the formulations of proven efficacy.Guidelines should clearly distinguish between the different areas in their recommendations regarding the intended information, e.g. mean values and/or ranges and confidence intervals. New approaches of granting limited waivers for BE studies (e.g. Biopharmaceutical Classification System (BCS)) should be expanded to consideration of pharmacokinetic properties of drugs (e.g. gastrointestinal metabolism, evidence for an absorption window, magnitude of first-pass effect, half-life) as already partly implemented in the German waiver concept, and further (scientifically) validated to achieve world-wide harmonisation (e.g. via ICH).

Aufgaben der klinischen Pharmakologie in der frühen Phase der Arzneimittelentwicklung

Zusammenfassung□ Auf dem Weg eines neuen Arzneimittels von der Idee zum Produkt kann man eine Einteilung in zwei Phasen vornehmen, die Wirkstoffindung und die Wirkstoffentwicklung.□ Dank des wissenschaftlichen Fortschritts ist es heute möglich, vereinfachte Testsysteme zu entwickeln, an denen eine Vielzahl von unbekannten Verbindungen auf eine biologische Wirkung geprüft werden kann. In der vorklinischen Phase der Arzneimittelentwicklung werden in pharmakologischen, toxikologischen und pharmakokinetischen Untersuchungen am Tier und in Invitro-Untersuchungen die Voraussetzungen für die Erstanwendung am Menschen geschaffen. Ist dann in der Phase I der klinischen Entwicklung ein erstes klinisch-pharmakologisches Profil der neuen Substanz erstellt worden, aufgrund dessen eine Entscheidung über die Fortsetzung der klinischen Prüfung getroffen werden kann, gilt es, in den Phasen II und III der klinischen Entwicklung die entscheidenden Fragen nach der Wirksamkeit und Sicherheit an einer großen Anzahl von Patienten mit der Zielindikation zu beantworten.□ Angesichts des Zeit- und Kostendruckes ist ein Hinauszögern der Entscheidung über Fortführung oder Abbruch eines Projektes erst in der späten Phase III der klinischen Entwicklung nicht mehr länger akzeptabel. Abweichend von der dargestellten traditionellen Einteilung sollte die Arzneimittelentwicklung auf zwei Stadien reduziert werden, ein exploratives, das die präklinische und frühe klinische Phase bis zur Phase IIa beinhaltet, und ein konfirmatorisches Stadium, das die weitere klinische Entwicklung beinhaltet.□ Die Entwicklung und der Einsatz von Surrogatparametern und Modellen als Ersatz für die klinischen Endpunkte Morbidität und Mortalität zur Prüfung des neuen therapeutischen Konzeptes und der optimalen Dosis sind entscheidend für eine erfolgreiche große klinische Prüfung im konfirmatorischen Stadium. Eine Identifizierung der Gene als Hauptursache für die große interindividuelle Variabilität und eine genetische Testung der Patienten vor der Wirksamkeitsprüfung in einer großen klinischen Studie könnten erheblich zur Optimierung der Arzneimittelentwicklung beitragen.□ Die klinische Pharmakologie muß als Bindeglied von Forschung und Entwicklung hier integriert werden und die Verantwortung übernehmen, um den ihr zukommenden wichtigen Aufgaben in der Arzneimittelentwicklung nachkommen zu können.Abstract□ The path of a new drug from the idea to the product may be divided into 2 phases, namely drug discovery and drug development.□ Due to the scientific progress new and simple methods could be developed to determine the biological efficacy of a large number of compounds. During the first part of drug development necessary requirements for the first use in man are met by performing preclinical pharmacological, toxicological and pharmacokinetic investigations in the animal and in in-vitro testing. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial is made, the aim of phases II and III is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication.□ Due to the continuously increasing time and costs of drug development, drug development should be streamlined combining preclinical and early clinical phases as an exploratory stage and later clinical development as a confirmatory stage.□ The development and appropriate use of surrogates and models may be helpful to determine drug actions in human and to assist in dose selection as the main requirement for a successful large clinical trial in the confirmatory stage. Identifying the genes responsible for the huge variations in how different patients respond to a drug, in terms of both the product’s effectiveness and its side effects, and genotyping patients before including in large clinical trials may prevent selecting the wrong patient population and avoid expensive repetition of these studies.□ Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in drug development. To reach this goal, clinical pharmacology must be fully integrated in the whole process of drug development from the candidate selection until the approval.The path of a new drug from the idea to the product may be divided into 2 phases, namely drug discovery and drug development. Due to the scientific progress new and simple methods could be developed to determine the biological efficacy of a large number of compounds. During the first part of drug development necessary requirements for the first use in man are met by performing preclinical pharmacological, toxicological and pharmacokinetic investigations in the animal and in in-vitro testing. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial is made, the aim of phases II and III is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Due to the continuously increasing time and costs of drug development, drug development should be streamlined combining preclinical and early clinical phases as an exploratory stage and later clinical development as a confirmatory stage. The development and appropriate use of surrogates and models may be helpful to determine drug actions in human and to assist in dose selection as the main requirement for a successful large clinical trial in the confirmatory stage. Identifying the genes responsible for the huge variations in how different patients respond to a drug, in terms of both the products effectiveness and its side effects, and genotyping patients before including in large clinical trials may prevent selecting the wrong patient population and avoid expensive repetition of these studies. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in drug development. To reach this goal, clinical pharmacology must be fully integrated in the whole process of drug development from the candidate selection until the approval.

Correlation of genotype, phenotype, and mRNA expression of CYP2D6 and CYP2C19 in peripheral blood leukocytes (PBLs).

INTRODUCTION The genetic polymorphism of drug metabolizing enzymes of the cytochrome P450 (CYP) families, especially CYP2D6 and CYP2C19, is the most important cause of variable responses of many drugs. Enzyme activity ranges from complete deficiency, so called poor metabolizers (PMs), to an ultrafast metabolism. While PMs and extensive metabolizers (EMs) can be well distinguished by genotyping, phenotyping is necessary to subdivide EMs from intermediate metabolizers (IMs). The aim of the study was to evaluate if messenger RNA (mRNA) concentration for CYP-enzymes in peripheral blood leukocytes (PBLs) will be predictive of systemic enzyme activity, allowing an easy and safe determination of metabolic activity. METHODS The genotype, phenotype, and mRNA-expression in PBLs were evaluated in 124 healthy Caucasian volunteers (males and females, age range 23 - 59 years) on three occasions (every 4 weeks). Genotyping was performed by Taqman allelic discrimination on the most common null alleles for CYP2D6 (*3, *4, *6, *7, and *8) and CYP2C19 (*2 and *3). For phenotyping CYP2D6, dextromethorphan/dextrorphan metabolic ratios were determined in collected urine (8 hours) after administration of 30 mg dextromethorphan. For phenotyping CYP2C19, we used the plasma concentration ratio of omeprazole/hydroxyomeprazole 4 hours after ingestion of 40 mg omeprazole. mRNA-expression in PBLs for CYP2D6 and CYP2C19 was measured by Taqman real-time PCR before medication and 4 hours afterwards. RESULTS Genotyping for CYP2D6 and CYP2C19 showed a regular distribution of EMs and PMs compared to studies of a comparable population. The median dextromethorphan/dextrorphan metabolic ratio was 0.47 in EMs/IMs and 2.29 in PMs. The median omeprazole/hydroxyomeprazole metabolic ratio was 3.06 in EMs/IMs and 35.29 in PMs. CYP2D6 and CYP2C19 mRNA expression was detected without evidence of correlation to the respective metabolic ratio. CONCLUSION The results do not support the concept of using mRNA expression profiles for CYP2D6 and CYP2C19 enzymes in PBLs for prediction of systemic enzyme activity.