Siv Jönsson

Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms

Objective To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. Methods A total of 104 pediatric patients (aged 0.36–16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. Results In the whole population, the mean±SD cyclosporine oral bioavailability was 0.38±0.09, volume of distribution was 2.3±0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88±0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51±0.13, and the hepatic extraction ratio was 0.24±0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64±0.09 in those with the ABCB1 c.2677GG genotype, 0.52±0.11 in those with the c.2677GT genotype, and 0.41±0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28±0.07, 0.36±0.07, and 0.44±0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations. Conclusions Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

ABSTRACT 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.

Long-Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

To improve cyclosporine dose individualization, the authors carried out a comprehensive analysis of the effects of clinical and genetic factors on cyclosporine pharmacokinetics in 176 children before and up to 16 years after renal transplantation. Pretransplantation test doses of cyclosporine were given intravenously and orally, followed by blood sampling for 24 hours. After transplantation, cyclosporine was quantified at trough, 2 hours postdose, or with dose‐interval curves. A 3‐compartment population pharmacokinetic model was used to describe the data. Cyclosporine oral bioavailability increased more than 1.5‐fold in the first month after transplantation, returning thereafter gradually to its initial value in 1 to 1.5 years. Moreover, older children receiving cyclosporine twice daily as the gelatin capsule microemulsion formulation had an about 1.25 to 1.3 times higher bioavailability than did the younger children receiving the liquid formulation thrice daily. In 91 children with genetic data after transplantation, patients carrying the NR1I2 g.‐25385C‐g.‐24381A‐g.‐205_‐200GAGAAG‐g.7635G‐g.8055C haplotype had about one‐tenth lower bioavailability, per allele, than did noncarriers (P = .039). The significance of the NR1I2 genotype warrants further study. In conclusion, by accounting for the effects of developmental factors (body weight), time after transplantation, and cyclosporine dosing frequency/formulation, it may be possible to improve individualization of cyclosporine dosing in children.

Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study.

A model characterizing the population pharmacokinetics (PK) of edoxaban and its major metabolite, M4, following a single oral dose of 15 mg administered to subjects with varying kidney function was developed. Thirty‐two subjects contributed with edoxaban plasma, edoxaban urine, and M4 plasma concentrations. Edoxaban urine concentrations allowed estimation of renal clearance, and high contribution of renal to total clearance enabled estimation of absolute oral bioavailability. A 2‐compartment model with delayed absorption and elimination parameterized as renal clearance linearly related to creatinine clearance (CLcr) and nonrenal clearance forming M4 described edoxaban PK. The PK of M4 was described with a 1‐compartment model. For a typical subject (70 kg; CLcr, 100 mL/min) bioavailability, clearance, and central and peripheral volume of distribution for edoxaban was estimated to 72.3%, 21.0 L/h, 95.4 L, and 54.3 L, respectively. For both edoxaban and M4, the model predicted systemic exposure to increase 57.0%, 35.0%, and 11.6% in a subject having CLcr of 30, 50, and 80 mL/min, respectively, compared with a subject having a CLcr of 100 mL/min. Concentration ratios (M4 over edoxaban) were predicted to vary with time after dose, but with minor influence of kidney function and body weight. Results were in agreement with previous analyses.

Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM and NLMIXED.

The application of proportional odds models to ordered categorical data using the mixed-effects modeling approach has become more frequently reported within the pharmacokinetic/pharmacodynamic area during the last decade. The aim of this paper was to investigate the bias in parameter estimates, when models for ordered categorical data were estimated using methods employing different approximations of the likelihood integral; the Laplacian approximation in NONMEM (without and with the centering option) and NLMIXED, and the Gaussian quadrature approximations in NLMIXED. In particular, we have focused on situations with non-even distributions of the response categories and the impact of interpatient variability. This is a Monte Carlo simulation study where original data sets were derived from a known model and fixed study design. The simulated response was a four-category variable on the ordinal scale with categories 0, 1, 2 and 3. The model used for simulation was fitted to each data set for assessment of bias. Also, simulations of new data based on estimated population parameters were performed to evaluate the usefulness of the estimated model. For the conditions tested, Gaussian quadrature performed without appreciable bias in parameter estimates. However, markedly biased parameter estimates were obtained using the Laplacian estimation method without the centering option, in particular when distributions of observations between response categories were skewed and when the interpatient variability was moderate to large. Simulations under the model could not mimic the original data when bias was present, but resulted in overestimation of rare events. The bias was considerably reduced when the centering option in NONMEM was used. The cause for the biased estimates appears to be related to the conditioning on uninformative and uncertain empirical Bayes estimate of interindividual random effects during the estimation, in conjunction with the normality assumption.

A diagnostic tool for population models using non-compartmental analysis

BACKGROUND AND OBJECTIVE Non-compartmental analysis (NCA) calculates pharmacokinetic (PK) metrics related to the systemic exposure to a drug following administration, e.g. area under the concentration-time curve and peak concentration. We developed a new package in R, called ncappc, to perform (i) a NCA and (ii) simulation-based posterior predictive checks (ppc) for a population PK (PopPK) model using NCA metrics. METHODS The nca feature of ncappc package estimates the NCA metrics by NCA. The ppc feature of ncappc estimates the NCA metrics from multiple sets of simulated concentration-time data and compares them with those estimated from the observed data. The diagnostic analysis is performed at the population as well as the individual level. The distribution of the simulated population means of each NCA metric is compared with the corresponding observed population mean. The individual level comparison is performed based on the deviation of the mean of any NCA metric based on simulations for an individual from the corresponding NCA metric obtained from the observed data. The ncappc package also reports the normalized prediction distribution error (NPDE) of the simulated NCA metrics for each individual and their distribution within a population. RESULTS The ncappc produces two default outputs depending on the type of analysis performed, i.e., NCA and PopPK diagnosis. The PopPK diagnosis feature of ncappc produces 8 sets of graphical outputs to assess the ability of a population model to simulate the concentration-time profile of a drug and thereby evaluate model adequacy. In addition, tabular outputs are generated showing the values of the NCA metrics estimated from the observed and the simulated data, along with the deviation, NPDE, regression parameters used to estimate the elimination rate constant and the related population statistics. CONCLUSIONS The ncappc package is a versatile and flexible tool-set written in R that successfully estimates NCA metrics from concentration-time data and produces a comprehensive set of graphical and tabular output to summarize the diagnostic results including the model specific outliers. The output is easy to interpret and to use in evaluation of a population PK model. ncappc is freely available on CRAN (http://cran.r-project.org/web/packages/ncappc/index.html/) and GitHub (https://github.com/cacha0227/ncappc/).

A rational approach for selection of optimal covariate-based dosing strategies

At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified.

Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism-the Hokusai-VTE phase 3 study

AIMS This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL(cr)) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations. METHODS The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance. RESULTS A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CL(cr). Compared with healthy volunteers, inter-compartmental clearance and the CL(cr) covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients. CONCLUSIONS The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.

Population Pharmacokinetic Modelling and Estimation of Dosing Strategy for NXY-059, a Nitrone Being Developed for Stroke

Background and objectivesNXY-059 (disufenton sodium, Cerovive®), a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.MethodsNXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CLCR). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CLCR or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfilment criteria and parsimony.PatientsPharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34–92 years with varying degrees of renal impairment (estimated CLCR 20–143 mL/min).Main outcome measures and resultsThe final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CLCR and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CLCR of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CLCR (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.ConclusionThe results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

Population pharmacokinetics of plasma-derived factor IX: procedures for dose individualization

Essentials A population pharmacokinetic model and sparse factor IX (FIX) levels may be used in dose individualization. FIX sampling schedules for dose individualization were explored and compared with fixed doses. Individual FIX doses were acceptably predicted with only two samples drawn post dose (days 2 and 3). Pharmacokinetic dose individualization resulted in better target attainment than a fixed‐dose regimen.