184: Population Pharmacokinetic Modelling of RP-6306, a Novel PKMYT1 Inhibitor, in Cancer Patients from a Phase 1 Dose Escalation Study

Statement of Purpose: RP-6306 is a novel, selective protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) inhibitor that is being evaluated in an ongoing first-in-human, Phase 1 dose-escalation study in patients with locally advanced or metastatic solid tumors. Here we characterize the pharmacokinetics (PK) of RP-6306 monotherapy or in combination with an ataxia telangiectasia-mutated - and rad3-related (ATR) inhibitor, camonsertib (RP-3500) using population pharmacokinetic (popPK) modeling and to identify significant covariates that affect RP-6306 PK.

Description of Methods & Materials: RP-6306 was administered orally once daily (QD) or twice daily (BID) as a single agent or in combination with camonsertib under fasted state. Plasma PK data from 1294 plasma samples obtained from 75 patients, including rich samples after a single-dose and multiple doses at steady state as well as sparse pre-dose samples, were included in the popPK analyses using nonlinear mixed-effects modeling (NONMEM) approach. Goodness-of -fit plots, prediction-corrected visual predictive checks and bootstrap analysis were used to evaluate the model. A graphical analysis was conducted to evaluate the effects of covariates (age, weight, sex, baseline creatinine clearance, co-administration of acid-reducing agents (i.e., proton pump inhibitors (PPIs)) on the individual absorption, distribution and elimination parameters (CL, Fa, MTT, Q and Vp).

Data & Results: A structural model with two-compartment disposition with transit compartments for absorption and first order elimination was developed. As RP-6306 displayed non-linear PK with saturable absorption at high doses, a parameter on the amount of drug absorbed (Fa) with dose as covariate was included in the model as random effect. Furthermore, to describe the dose-Fa relationship, a linear dose-covariate model that describes the covariate-random effect correlation was used. The residual variability was best characterized by log-normal model. The final base model adequately fit the observed PK data. Graphical covariate analyses suggested no effect of age, weight, and baseline creatinine clearance on the PK parameters of RP-6306. The results suggested that female patients appear to have greater absorption and less clearance of RP-6306 than male patients. In addition, the coadministration of PPIs appear to affect the absorption of RP-6306, which could be attributed to RP-6306’s pH-dependent solubility. However, further simulations did not reveal clinically significant impact of sex and the concomitant use of PPIs on the exposure of RP-6306, suggesting no need of dose adjustment in specific populations. The parameters in single agent and combination with camonsertib appear similar.

Interpretation, Conclusion or Significance: A novel population PK model structure to characterize the non-linear absorption of RP-6306 was successfully developed. The model can adequately describe the observed RP-6306 PK data in cancer patients. The interim covariate analysis did not suggest a need of dose adjustment based on patients’ intrinsic (age, weight, sex, renal function) and extrinsic factors (concomitant use of PPIs).

Disclosures: