The British Journal of Clinical Pharmacology: The first 50 years.

The British Journal of Clinical Pharmacology celebrates its 50th anniversary of publication in 2023. Here four previous Editors-in-Chief and the current Editor reflect on the Journal's history and the changes that have occurred during that time.

When Regional Anesthesia Met Pharmacokinetics.

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.

A series acceleration algorithm for the gamma-Pareto (type I) convolution and related functions of interest for pharmacokinetics.

The gamma-Pareto type I convolution (GPC type I) distribution, which has a power function tail, was recently shown to describe the disposition kinetics of metformin in dogs precisely and better than sums of exponentials. However, this had very long run times and lost precision for its functional values at long times following intravenous injection. An accelerated algorithm and its computer code is now presented comprising two separate routines for short and long times and which, when applied to the dog data, completes in approximately 3 min per case. The new algorithm is a more practical research tool. Potential pharmacokinetic applications are discussed.

Prediction of olanzapine exposure in individual patients using physiologically based pharmacokinetic modelling and simulation.

AIM: The aim of the present study was to predict olanzapine (OLZ) exposure in individual patients using physiologically based pharmacokinetic modelling and simulation (PBPK M&S). METHODS: A 'bottom-up' PBPK model for OLZ was constructed in Simcyp® (V14.1) and validated against pharmacokinetic studies and data from therapeutic drug monitoring (TDM). The physiological, demographic and genetic attributes of the 'healthy volunteer population' file in Simcyp® were then individualized to create 'virtual twins' of 14 patients. The predicted systemic exposure of OLZ in virtual twins was compared with measured concentration in corresponding patients. Predicted exposures were used to calculate a hypothetical decrease in exposure variability after OLZ dose adjustment. RESULTS: The pharmacokinetic parameters of OLZ from single-dose studies were accurately predicted in healthy Caucasians [mean-fold errors (MFEs) ranged from 0.68 to 1.14], healthy Chinese (MFEs 0.82 to 1.18) and geriatric Caucasians (MFEs 0.55 to 1.30). Cumulative frequency plots of trough OLZ concentration were comparable between the virtual population and patients in a TDM database. After creating virtual twins in Simcyp®, the R2 values for predicted vs. observed trough OLZ concentrations were 0.833 for the full cohort of 14 patients and 0.884 for the 7 patients who had additional cytochrome P450 2C8 genotyping. The variability in OLZ exposure following hypothetical dose adjustment guided by PBPK M&S was twofold lower compared with a fixed-dose regimen - coefficient of variation values were 0.18 and 0.37, respectively. CONCLUSIONS: Olanzapine exposure in individual patients was predicted using PBPK M&S. Repurposing of available PBPK M&S platforms is an option for model-informed precision dosing and requires further study to examine clinical potential.

Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia.

Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were <10µM. LAP, PAZ, REG and SOR inhibited UGT1A1-catalysed bilirubin glucuronidation with mean IC50 values ranging from 34nM (REG) to 3734nM (PAZ). Subsequent kinetic experiments confirmed that REG and SOR were very potent inhibitors of human liver microsomal ß-estradiol glucuronidation, an established surrogate for bilirubin glucuronidation, with mean Ki values of 20 and 33nM, respectively. Ki values for LAP and PAZ were approximately 1- and 2-orders of magnitude higher than those for REG and SOR. REG and SOR were equipotent inhibitors of human liver microsomal UGT1A9 (mean Ki 678nM). REG and SOR are the most potent inhibitors of a human UGT enzyme identified to date. In vitro-in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely.

Personalized Drug Dosage - Closing the Loop.

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.

In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism.

Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of schizophrenia and related psychoses. The metabolism of OLZ is complex and incompletely characterized. This study aimed to elucidate the enzymes and pathways involved in the metabolism of OLZ and to determine the kinetics of OLZ oxidation and glucuronidation by human liver microsomes, recombinant cytochrome P450 (rP450) enzymes, and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. An ultra-performance liquid chromatography-mass spectrometry method was developed and validated to quantify OLZ, its four oxidative metabolites (N-desmethyl-OLZ, 2-hydroxymethyl-OLZ, 7-hydroxy-OLZ, and OLZ-N-oxide), and two N-glucuronides (OLZ-10-N-glucuronide and OLZ-4'-N-glucuronide). Consistent with previous reports, UGT1A4, CYP1A2, and flavin-containing monooxygenase 3 play major roles in catalyzing the formation of OLZ-10-N-glucuronide, 7-hydroxy-OLZ, and OLZ-N-oxide, respectively. In addition, a previously uncharacterized major contribution of CYP2C8 to OLZ-N-demethylation was demonstrated. The kinetics of OLZ metabolite formation (Km and Vmax) by human liver microsomes, rP450 enzymes, and rUGT enzymes were characterized in the presence of bovine serum albumin [2% (w/v)]. Consistent with the known effect of bovine serum albumin on CYP1A2, CYP2C8, and UGT1A4 activities, Km values reported here are lower than previously reported values for OLZ metabolic pathways. In addition to CYP1A2-mediated OLZ-N-demethylation, these results suggest that other P450 enzymes, particularly CYP2C8, contribute significantly to oxidative OLZ metabolism through catalysis of OLZ-N-demethylation.

Does age affect gastric emptying time? A model-based meta-analysis of data from premature neonates through to adults.

PURPOSE: Gastric emptying (GE) is often reported to be slower and more irregular in premature neonates than in older children and adults. The aim of this study was to investigate the impact of age and other covariates on the rate of GE. METHODS: The effect of age on the mean gastric residence times (MGRT) of liquid and solid food was assessed by analysing 49 published studies of 1457 individuals, aged from 28 weeks gestation to adults. The data were modelled using the nonlinear mixed-effects approach within NONMEM version 7.2 (ICON, Dublin, Ireland), with evaluation of postnatal age, gestational age and meal type as covariates. A double Weibull function was selected as a suitable model since it could account for the typical biphasic nature of GE. RESULTS: Age was not a significant covariate for GE but meal type was. Aqueous solutions were associated with the fastest emptying time (mean simulated gastric residence time of 45 min) and solid food was associated with the slowest (98 min). CONCLUSIONS: These findings challenge the assertion that GE is different in neonates, as compared with older children and adults due to age, and they reinforce the significance of food type in modulating GE.

A re-evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data.

BACKGROUND AND OBJECTIVES: 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. METHOD: 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. RESULTS: 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). CONCLUSIONS: 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.

Differences in cytochrome p450-mediated pharmacokinetics between chinese and caucasian populations predicted by mechanistic physiologically based pharmacokinetic modelling.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment.

The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.

Research priorities in pharmacokinetics.

An opinion is expressed on the past, present and future roles of pharmacokinetic-pharmacodynamic research in the context of UK clinical pharmacology. On the basis of its current constitution, it seems unlikely that this area of research will be driven from within academic clinical pharmacology in the UK. Therefore, in order to bring its expertise and experience to bear effectively on the evolving emphasis on translational medicine and modelling and simulation, this community would need to reach out beyond its current preoccupations to increase interactions with the next generation of pharmacokineticists and pharmacometricians.