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

Schaefer, Hans; Heinig, Roland; Ahr, G.; Adelmann, Holger G.; Tetzloff, W; Kuhlmann, J.

doi:10.1007/s002280050233

Cited by 23 publications

(10 citation statements)

References 8 publications

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“…We analyzed two classes of anti-hypertensives: the direct-acting calcium channel blockers [15, 16] and the indirect-acting angiotensin-II antagonists [17]. We focused on drugs approved between 1980 and 2007 with IR drug or active metabolite terminal half lives in the range of 6-15 hours.…”

Section: Discussionmentioning

confidence: 99%

Intermittent drug dosing intervals guided by the operational multiple dosing half lives for predictable plasma accumulation and fluctuation

Grover

Benet

2011

J Pharmacokinet Pharmacodyn

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Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives.

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Section: Discussionmentioning

confidence: 99%

Intermittent drug dosing intervals guided by the operational multiple dosing half lives for predictable plasma accumulation and fluctuation

Grover

Benet

2011

J Pharmacokinet Pharmacodyn

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“…Food may alter the rate of delivery of a drug into the systemic circulation. For example, the clinical relevance of a food interaction with a controlled release dosage form of nisoldipine (an antihypertensive) was investigated by Schaefer et al (63) Based on PK/PD modeling the authors concluded that additional decrease in blood pressure occurs with food intake that could result in patients experiencing a mild adverse event. To minimize variability in drug exposure and response in later phases, the extent of ''food effect'' on the pharmacokinetics (and pharmacodynamics) of the drug product needs to be studied early (64).…”

Section: Food and Gender Effect Studiesmentioning

confidence: 99%

A Rational Approach to Drug Development: The Exploratory Phase

Ette

Garg

Jayaraj

2004

Clinical Research and Regulatory Affairs

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Drug development is a complex process, and added to it is the sophisticated new technologies and approaches to drug design, of which rational drug design is the epitome. A low success rate for investigational new drugs calls for improvement in drug discovery and development processes. Implementing knowledge driven drug development strategies founded on informative, powerful, and robust studies would greatly improve the drug discovery and development processes. Knowledge driven drug discovery and development that emphasizes a learn-confirm-learn paradigm is proposed as the rational basis for drug development. Although clinical drug development is usually divided into Phases I, II, III, and IV; it should rather be defined by those studies necessary to obtain data to answer the fundamental development decision questions: ''Is the new molecular entity tolerated and at what dose range?'' and ''Does it show efficacy for intended use within the tolerated dose range?'' In setting out to answer these questions during drug development, we propose that the learn-confirm-learn paradigm of drug development provides the most appropriate answers to these questions and hence a rational and optimal drug development process (DDP). The exploratory phase of drug development provides the Clinical Research and Regulatory Affairs Downloaded from informahealthcare.com by Kainan University on 04/08/15For personal use only.answer to the first question, and answers the second question in part through a welldesigned proof of concept study.

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“…Nisoldipine is commonly used in clinical practice to treat hypertension and coronary heart disease. [4][5][6] Nisoldipine exhibits high pharmacological activity that is associated with low therapeutic doses, low bioavailability, and a high distribution volume, and thus requires a highly sensitive analytical method. Several analytical methods based on liquid or gas chromatography coupled with mass spectrometry have been introduced for the quantification of nisoldipine in human plasma.…”

Section: Introductionmentioning

confidence: 99%

Liquid Chromatography/Positive-Ion Electrospray Tandem Mass Spectrometry Assay for Nisoldipine in Human Plasma and Its Application to a Pharmacokinetic Study

Liu

Teng

Yuan

et al. 2011

Journal of Liquid Chromatography & Related Technologies

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& A rapid, sensitive, and specific method was developed for the identification and quantitation of the calcium antagonist nisoldipine in human plasma by liquid chromatography coupled with tandem mass spectrometry using nimodipine as an internal standard. Nisoldipine was extracted from human plasma (0.2 mL) by a liquid=liquid procedure using diethyl ether as the eluent. The mass spectrometer was operated in the multiple reaction-monitoring scan mode using an electrospray ionization source. The analyte and internal standard could be separated in 2 min on a C 18 analytical column with a mobile phase of acetonitrile:water (66:34, v=v) at a flow rate of 0.4 mL Á min À1 . The calibration curve of nisoldipine in human plasma was linear over the range from 0.1 to 30 ng Á mL À1 (r 2 ! 0.9994). The precision, determined as the relative standard deviation of replicate quality controls, was 9.35% (0.2 ng Á mL À1 ), 11.61% (2.0 ng Á mL À1 ), and 4.68% (20 ng Á mL À1 ). This method was successfully applied to pharmacokinetic studies and determination of nisoldipine concentration in vivo.

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

Cited by 23 publications

References 8 publications

Intermittent drug dosing intervals guided by the operational multiple dosing half lives for predictable plasma accumulation and fluctuation

Intermittent drug dosing intervals guided by the operational multiple dosing half lives for predictable plasma accumulation and fluctuation

A Rational Approach to Drug Development: The Exploratory Phase

Liquid Chromatography/Positive-Ion Electrospray Tandem Mass Spectrometry Assay for Nisoldipine in Human Plasma and Its Application to a Pharmacokinetic Study

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