Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.

No abstract

What is already known about this subject • Ciclosporin is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. • It is likely that the inter‐ and intraindividual variability in ciclosporin pharmacokinetics and dose requirements is even larger in children than in adults as a result of variation in biological maturation status. • However, data on the developmental pharmacokinetics of ciclosporin, as well as other CYP3A4 substrate drugs, in children are scarce. What this study adds • Adult CYP3A4 activity seems to be reached by the age of 6–12 months, and allometrically scaled body weight is a good predictor of the hepatic clearance of ciclosporin, a CYP3A4 substrate. • Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. • These conclusions were reached using a robust modelling approach (NONMEM) with rich paediatric pharmacokinetic data collected after full i.v. and p.o. profiles. Aims To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin. Methods Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg−1) and orally (10 mg kg−1) on separate occasions followed by blood sampling for 24 h. Results A three‐compartment model with first‐order absorption without lag‐time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age‐related changes in oral bioavailability or in BW‐normalized V were seen. The BW‐normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW3/4) removed its relationship to age. Conclusion The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.

Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.In order to optimize treatment regimens, there is an urgent need to critically evaluate the pharmacokinetics and corresponding effects of the antituberculosis drugs among patients with tuberculosis. Population pharmacokinetic modeling is considered an efficient means to summarize data in terms of typical parameter estimates, effects of covariates (e.g., body weight, sex, and gender), and unexplained variability. Furthermore, population pharmacokinetic models are valuable for simulation purposes and enable alternative dose regimens for subpopulations aiming at specific pharmacokinetic target levels to be assessed to establish more effective treatment. The present analysis was designed to describe the population pharmacokinetics of ethambutol (EMB) in a South African patient population, including the characterization of interindividual variability (IIV) and interoccasion variability (IOV) and exploration of the causes of variability, which have not been addressed in previous models (27,39).EMB is a bacteriostatic agent with a mechanism of action that has been suggested to occur by inhibition of mycobacterial cell wall synthesis. The primary role of EMB in the first-line four-drug antitubercular regimen (i.e., EMB in combination with rifampin, isoniazid, and pyrazinamide) is to protect aga...