A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, ...computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed.
The perceived failure of new drug development has been blamed on deficiencies in in vivo studies of drug efficacy and safety. Prior simulation of the potential exposure of different individuals to a ...given dose might help to improve the design of such studies. This should also help researchers to focus on the characteristics of individuals who present with extreme reactions to therapy. An effort to build virtual populations using extensive demographic, physiological, genomic and in vitro biochemical data to simulate and predict drug disposition from routinely collected in vitro data is outlined.
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ...ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval.
We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies.
Demographic and physiological data for Chinese, along with information on CYP abundances and the frequencies of associated genetic polymorphisms in Chinese, were collated from literature sources and incorporated within the Simcyp Population-based Simulator(®) (v11.1). Default Simcyp parameter values for a virtual Caucasian population and for model compounds metabolized principally by specific CYPs were used as the point of reference. The drugs and the main CYPs involved in their metabolism were phenacetin (CYP1A2), desipramine (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), and alprazolam and midazolam (CYP3A). Hydroxy bupropion formation was used as a more sensitive marker of CYP2B6 activity than bupropion kinetics. Observed plasma drug concentration-time profiles and pharmacokinetic parameters after oral and, where possible, intravenous dosing were obtained from published in vivo studies in both Chinese and Caucasian subjects. Virtual subjects generated within Simcyp were matched to the subjects used in the in vivo studies with respect to age, sex, dosage and, where possible, CYP phenotype frequency. Predicted and observed plasma drug concentrations and weight-normalized clearances were compared between the ethnic groups.
Significant differences were identified between Chinese and Caucasian populations in the frequency of CYP2C19 poor metabolizers (PMs) Chinese 13 %; Caucasian 2.4 %, CYP2D6 PMs and intermediate metabolizers (IMs) Chinese PMs 0.3 %, IMs 39 %; Caucasian PMs 8 %, IMs <1 %, the hepatic abundance of CYP2C19 (mean values: Chinese 8 pmol/mg; Caucasian 14 pmol/mg) and liver weight (mean values: Chinese 1198 g; Caucasian 1603 g). The observed plasma drug concentration-time profiles and weight-normalized clearances were predicted with reasonable accuracy (100 % within twofold; 89 % within 1.5-fold) in both ethnic groups. The predicted phenacetin, tolbutamide, omeprazole, desipramine, midazolam (intravenous), midazolam (oral), alprazolam (intravenous) and alprazolam (oral) clearances were 36, 25, 51, 43, 24, 17, 21 and 22 % lower, respectively, in Chinese than in Caucasians; the observed clearances were 28, 2, 75, 42, 19, 62, 20 and 21 % lower, respectively. Predicted and observed formation of hydroxy bupropion was lower in Caucasians than in Chinese (6 and 20 %, respectively). Differences between ethnic groups were less after normalization for body weight.
The results of this study indicate the value of simulation based on mechanistic physiologically based pharmacokinetic modelling (PBPK) in anticipating the likely extent of any differences in the kinetics of CYP substrates in Chinese and Caucasian populations arising from demographic, physiological and genetic differences.
Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in paediatric physiologically based pharmacokinetic models, have been ...reported to under-predict the in vivo clearances of some model substrates in neonates and infants.
We report ontogeny functions for these enzymes as paediatric to adult relative intrinsic clearance per mg of hepatic microsomal protein, based on the deconvolution of in vivo pharmacokinetic data and by accounting for the impact of known clinical condition on hepatic unbound intrinsic clearance for caffeine and theophylline as markers of CYP1A2 activity and for midazolam as a marker of CYP3A4 activity.
The function for CYP1A2 describes an increase in relative intrinsic metabolic clearance from birth to 3 years followed by a decrease to adult values. The function for CYP3A4 describes a continuous rise in relative intrinsic metabolic clearance, reaching the adult value at about 1.3 years of age. The new models were validated by showing improved predictions of the systemic clearances of ropivacaine (major CYP1A2 substrate; minor CYP3A4 substrate) and alfentanil (major CYP3A4 substrate) compared with those using a previous ontogeny function based on in vitro data (alfentanil: mean squared prediction error 3.0 vs. 6.8; ropivacaine: mean squared prediction error 2.3 vs.14.2).
When implementing enzyme ontogeny functions, it is important to consider potential confounding factors (e.g. disease) that may affect the physiological conditions of the patient and, hence, the prediction of net in vivo clearance.
Prediction of the exposure of neonates, infants and children to xenobiotics is likely to be more successful using physiologically based pharmacokinetic models than simplistic allometric scaling, ...particularly in younger children. However, such models require comprehensive information on the ontogeny of anatomical, physiological and biochemical variables; data that are not available from single sources. The Simcyp software integrates demographic, genetic, physiological and pathological information on adults with in vitro data on human drug metabolism and transport to predict population distributions of drug clearance (CL) and the extent of metabolic drug-drug interactions. The algorithms have now been extended to predict clearance and its variability in paediatric populations by incorporating information on developmental physiology and the ontogeny of specific cytochrome P450s.
Values of the clearance (median and variability) of 11 drugs (midazolam oral and intravenous, caffeine, carbamazepine, cisapride, theophylline, diclofenac, omeprazole, S-warfarin, phenytoin, gentamicin and vancomycin) were predicted for 2,000 virtual subjects (birth to 18 years). In vitro enzyme pharmacokinetic parameters (maximum rate of metabolism Vmax and Michaelis-Menten constant Km) and in vivo clearance data were obtained from the literature.
In neonates 70% (7/10) of predicted median clearance values were within 2-fold of the observed values. Corresponding results for infants, children and adolescents were 100% (9/9), 89% (17/19) and 94% (17/18), respectively. Predicted variability (95% confidence interval) was within 2-fold of the observed values in 70% (7/10), 67% (6/9), 63% (12/19) and 55% (10/18) of cases, respectively. The accuracy of the physiologically based model incorporated in the Simcyp software was superior to that of simple allometry, especially in children <2 years old.
The in silico prediction of pharmacokinetic behaviour in paediatric patients is not intended to replace clinical studies. However, it provides a valuable aid to decision-making with regard to first-time dosing in children and study design. The clinical study then becomes 'confirmatory' rather than 'exploratory'.
Pharmacokinetics of Local Anaesthetic Agents. By Tucker GT, Mather LE. Br J Anaesth 1975; 47(suppl 1):213-24 Information derived from measurements of blood concentrations of local anaesthetics can be ...extended by the application of pharmacokinetic analysis. A better understanding of quantitative aspects of the disposition and absorption of these drugs should assist the anaesthetist in deciding the optimal agent and dosage for regional block techniques.
Metformin disposition—A 40‐year‐old mystery Tucker, Geoffrey T.; Wesolowski, Carl A.
British journal of clinical pharmacology,
August 2020, Letnik:
86, Številka:
8
Journal Article
Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. ...Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis.
Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations.
There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold).
The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.
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