Simultaneous Modeling of Biomarker and Toxicity Response Predicted Optimal Regimen of Guadecitabine (SGI-110) in Myeloid Malignancies.

Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure-response analyses of longitudinal measures of long interspersed nucleotide element-1 (LINE-1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5-day regimen of 60 mg/m2 with partial recovery before the next cycle, whereas the nadir of 90 mg/m2 on the same schedule was below 100/µl. ANC following a 60 mg/m2 10-day regimen was predicted to be suppressed below 100/µl as long as treatment continued without recovery. The developed models provided useful tools to assist simultaneous evaluation of the relative dynamics of the two effects (DNA demethylation and the effect on ANC).

Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies.

AIMS: The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule. METHODS: Plasma samples and longitudinal tumour size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30-450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modelling was employed to develop the population pharmacokinetic and pharmacodynamic model. RESULTS: The pharmacokinetics were best described by a one compartment disposition model and transit compartments accounting for the lag time in absorption. The typical population oral clearance and volume of distribution estimates with their between-subject variability (BSV) were 10 l h(-1) (BSV 26%) and 108 l (BSV 28%), respectively. The estimated optimal number of transit compartments was 8.1, with a mean transit time to the absorption compartment of 1.28 h (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumour growth was modelled using a turnover model characterized by a zero order growth rate of 0.581 cm week(1) and a first order death rate of 0.0123 week(-1) . BYL719 inhibited tumour growth with an IC50 of 100 ng ml(-1) (BSV 154%). Model-based predictions showed potential for additional anti-tumour activity of twice daily dosing at total daily dose below 400 mg, but a loss of efficacy if administered less frequently than once daily. CONCLUSIONS: The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719.

Time-dependent clearance of mycophenolic acid in renal transplant recipients.

AIMS: Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects. METHODS: One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation. RESULTS: The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL. CONCLUSIONS: By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis.

AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS: Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS: This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.

Population pharmacokinetic modelling of Emfilermin (recombinant human leukaemia inhibitory factor, r-hLIF) in healthy postmenopausal women and in infertile patients undergoing in vitro fertilization and embryo transfer.

AIMS: The aim of this analysis was to develop a population pharmacokinetic model for Emfilermin (recombinant human leukaemia inhibitory factor, r-hLIF) following subcutaneous administration to healthy postmenopausal women and to infertile patients undergoing in vitro fertilization and embryo transfer (IVF-ET). METHODS: Data from three studies, a single and a repeat dose Phase I study in postmenopausal women as well as a proof of concept study in patients undergoing in vitro fertilization and embryo transfer were combined and analyzed. The structural pharmacokinetic model was developed using the rich data from the Phase I studies and the full pharmacostatistical model was then derived using all the data. RESULTS: The pharmacokinetics of r-hLIF after repeated subcutaneous administration were described by a one-compartment disposition model with a zero order input. The duration of the absorption phase was short (0.8 h) and invariant. The apparent clearance in postmenopausal women was 57 l h(-1) (CV = 17%). In in vitro fertilization and embryo transfer patients, the apparent clearance was decreased by 35% compared with postmenopausal women. The apparent volume of distribution was 235 l (interindividual CV = 28%) and exhibited an interoccasion variability of 23%. It increased (for weight above 62 kg) or decreased (for weight below 62 kg) by 29% for every 10 kg body weight. The median posthoc estimates of apparent clearance and volume of distribution and their variability were consistent with the population estimates. In postmenopausal women, the results were consistent with those obtained by noncompartmental analysis. The residual variability on r-hLIF serum concentrations was 20%. CONCLUSIONS: The pharmacokinetics of r-hLIF after repeated SC administration were described by a one compartment disposition model, with zero order input, in postmenopausal women and those undergoing IVF or intracytoplasmic sperm injection and embryo transfer. Absorption of r-hLIF was rapid as was its subsequent clearance. The apparent volume of distribution of r-hLIF was moderate to high, depended on body weight and showed interoccasion variability.