Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

Abstract

Simulations predicted lower steady-state peak/trough olaparib exposure through 24-36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors

“…In our trial, the pharmacokinetic analysis revealed no drug interactions for lurbinectedin or olaparib. The mean olaparib total body clearance of 7 L/h in our trial was comparable with the literature, with values of 5.1 L/h and 8.6 L/h 31 . However, the terminal half-life in our trial was shorter (3 h) than previously reported (between 7 and 12 h), probably because these values were obtained from single-dose trials; while in this trial the NCA used samples until 6 h.…”

Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations

“… No in vitro data are available to estimate V ss in patients, therefore V ss of olaparib was estimated to be 0.378 L/kg using the Rodgers and Rowland 2007 method; this value is in a reasonable agreement with apparent volume distribution (0.438 L/kg) estimated using a population pharmacokinetic approach …”

“…PBPK‐modeling software (Simcyp, v. 16.1) was used to build PBPK models for simulating the human exposure of olaparib tablet or capsule ( Table ) …”

“…PBPK-modeling software (Simcyp, v. 16.1) was used to build PBPK models for simulating the human exposure of olaparib tablet or capsule ( Table 5). [37][38][39][40] Based on olaparib drug disposition and DDI mechanisms, the PBPK tablet model was built in three stages. First, the model was developed using in vitro and physical-chemistry data with a derived value of in vivo human intestinal effective permeability (P eff,human ) parameter to drive first-order absorption from an oral dose (Supplementary Supporting Information).…”

“…Predefined acceptance criteria to assess the predictive performance of the 37 ; this value is in a reasonable agreement with apparent volume distribution (0.438 L/kg) estimated using a population pharmacokinetic approach. 38 For in vitro dissolution information on the tablet and capsule formulations, please see the Supplementary Materials. B/P, blood-to-plasma ratio; CL int , intrinsic clearance; CL po , apparent oral clearance; EC 50 , half-maximal effective concentration; E max , maximum achievable response; f u,gut , fraction unbound in gut enterocytes; f u,inc , fraction unbound in the incubation; f u,mic , fraction unbound in microsomes; f u,plasma , fraction unbound in plasma; HLM, human liver microsomes; K I , inhibitory constant for time-dependent inhibition; K i , inhibitory constant for reversible inhibition; K inact , rate of enzyme inactivation; MW, molecular weight; P eff,man , human intestinal effective permeability; pK a , acid dissociation constant (logarithmic scale); V ss , volume of distribution at steady state.…”