Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors

Abstract

Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data from 269 patients with cancer treated with oral glasdegib doses ranging from 5 to 640 mg/d. Nonlinear mixed-effects modeling was conducted using NONMEM (v.7.3) and Perl-speaks NONMEM (v.4.2.0). The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 6.27 L/h, 3.32 L, and 279.2 L, respectively. Age, sex, race, and hepatic function were not significant covariates on glasdegib pharmacokinetic parameters. Baseline body weight, percentage bone marrow blasts, creatinine clearance, and use of moderate or strong cytochrome P450 3A inhibitors were statistically significant covariates on apparent total clearance; however, the magnitude of the effects was not considered clinically meaningful.

Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers

“…Given that the participants were in good general health, aside from differences in renal function, no clinically meaningful changes in laboratory parameters or vital signs were observed between the renal impairment and normal renal function groups. The current study data support the findings from a population PK analysis of pooled data from patients with hematologic cancer and advanced solid tumor across Phase I and Phase II studies [13]. In the pooled analyses, the median glasdegib CL/F estimate was similar between patients with normal renal function (6.5 L/h) and mild renal impairment (6.2 L/h); therefore, an increase in glasdegib exposure was not expected with mild renal impairment and was not assessed in the current study.…”

Evaluation of the Relationship of Glasdegib Exposure and Safety End Points in Patients With Refractory Solid Tumors and Hematologic Malignancies

“…Dosing information, demographic and safety laboratory data, and disease assessments including event and time of event were derived from source data collected from the 3 clinical studies. Individual PK parameters estimated previously 14 were used to derive different glasdegib exposure metrics.…”

“…The pharmacokinetics (PK) of glasdegib has been fully characterized and reported elsewhere 14 . Individual post hoc estimates based on the population PK model for glasdegib were used to derive glasdegib exposures for individual patients.…”

“…Exposure‐response (E‐R) modeling analysis for selected safety end points, based on incidence or clinical relevance for glasdegib‐treated patients, was conducted using data from 3 clinical studies, in which glasdegib was used as monotherapy or in combination with chemotherapy. The E‐R analysis aimed to estimate the association between glasdegib exposure (through several exposure metrics estimated using the final population PK analysis 14 at the time the highest event grade recorded) and the incidence of the safety cluster terms dysgeusia , muscle spasms , renal toxicity , and QT interval prolonged ; it also aimed to evaluate the effect of intrinsic and extrinsic factors (covariates) on the E‐R relationship for each of the safety end points.…”

An evaluation of overall survival in patients with newly diagnosed acute myeloid leukemia and the relationship with glasdegib treatment and exposure

“…To derive summary measures of glasdegib exposure, individual empirical Bayes estimates of PK parameters were generated from a previously described population PK model [16]. Because duration of treatment may significantly impact efficacy, glasdegib exposure metrics that were not time dependent or that were earlier in the treatment course were selected in the exposure-response analysis.…”