Poe-Hirr Hsyu

The application of accelerator mass spectrometry to absolute bioavailability studies in humans: simultaneous administration of an intravenous microdose of 14C-nelfinavir mesylate solution and oral nelfinavir to healthy volunteers.

The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of 14C‐nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11‐day study period. The moderate bioavailability of nelfinavir was due to significant first‐pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first‐pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand‐fold dose reduction of 14C‐nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non–small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non–small cell lung) and median overall survival (pancreas). Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens. Clin Cancer Res; 18(4); 1092–100. ©2011 AACR.

Population Pharmacokinetic and Pharmacodynamic Analysis of Bosutinib

Bosutinib is an orally active, competitive inhibitor of Src/Abl tyrosine kinases. A population pharmacokinetic model was developed using data pooled from 3 studies of patients (n = 870) with solid tumors or Philadelphia chromosome-positive leukemia. Patients (aged 18-91 y, weighing 35-221 kg) who received bosutinib 50 to 600 mg orally with food each contributed 6-9 pharmacokinetic samples. The final pharmacokinetic model was a linear two-compartment model with first-order absorption, an absorption lag-time, and dose-dependent bioavailability. Oral absorption was relatively slow, with a half-time of 1.14 h and a lag-time of 0.87 h; time to peak concentration was 5-6 h. Apparent clearance was 120 L/h. The apparent volume of the peripheral compartment was large with a slow turnover; alpha and beta half-lives were 19 h and 290 days, respectively. All parameters were estimated with acceptable precision (standard error <30%). No tested covariate (protocol, baseline demographic/clinical characteristics, or laboratory results) explained the high inter-individual variability of bosutinib pharmacokinetics. Therefore, adjusting bosutinib dose for body size (weight, surface area) would not provide benefit over fixed dosing. Using this exposure model in pharmacodynamic assessment of one study, adverse event incidence was shown to be similar in overall and bosutinib-responsive populations.

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug–Drug and Drug–Disease Interactions

Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome–positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of bosutinib; 2) verify and refine the PBPK models based on clinical study results of bosutinib single-dose drug–drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug–disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration. Results showed that the PBPK models adequately predicted bosutinib oral exposures in patients after single- and multiple-dose administrations. The PBPK models also reasonably predicted changes in bosutinib exposures in the single-dose DDI and DDZI results, suggesting that the PBPK models were sufficiently developed and verified based on the currently available data. Finally, the PBPK models predicted 2- to 4-fold increases in bosutinib exposures by moderate CYP3A inhibitors, as well as comparable increases in bosutinib exposures in renally and hepatically impaired patients between single- and multiple-dose administrations. Given the challenges in conducting numerous DDI and DDZI studies of anticancer drugs in patients, we believe that the PBPK models verified in our study would be valuable to reasonably predict bosutinib exposures under various scenarios that have not been tested clinically.

Absolute Bioavailability of Bosutinib in Healthy Subjects From an Open‐Label, Randomized, 2‐Period Crossover Study

This study evaluated the absolute bioavailability of bosutinib and assessed its safety and tolerability after single‐dose oral and intravenous administration. In this phase 1 open‐label, 2‐sequence, 2‐period crossover study, healthy, fed subjects aged 18−55 years were randomized to 1 of 2 treatment sequences (n = 7/sequence): oral bosutinib (100 mg × 5) followed by intravenous bosutinib (120 mg in approximately 240 mL over 1 hour), with a ≥14‐day washout, or intravenous bosutinib and then oral bosutinib. Results of plasma pharmacokinetics analyses demonstrated that exposure to intravenous bosutinib was 3‐fold higher than for oral bosutinib (16.2 and 5.5 ng·h/mL/mg, respectively), and mean terminal half‐life was similar (35.5 and 31.7 hours). The ratio of adjusted geometric means (90%CI) for the dose‐normalized area under the plasma concentration–time profile (AUC0−∞/D) was 33.85% (30.65%‒37.38%). Most treatment‐emergent adverse events (AEs) were mild in severity. Gastrointestinal (GI) AEs occurred in 9 of 13 subjects given oral bosutinib, whereas no subjects given intravenous bosutinib experienced GI AEs, suggesting bosutinib present in the GI tract had an effect. Bosutinib exhibited an absolute bioavailability of 33.85% based on the ratio of AUC0−∞/D. Both oral and intravenous bosutinib were safe and well tolerated in healthy, fed adult subjects.

Abstract A195: A population pharmacokinetic (PPK) model of bosutinib (BOS).

BOS is an orally active, dual Src/Abl kinase inhibitor. BOS has demonstrated efficacy and acceptable safety in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemia. A PPK model was developed for BOS using pooled clinical data from a phase 1 trial of pts with advanced solid tumors given BOS 50 to 600 mg/d with food; a phase 1/2 trial of pts with tyrosine kinase inhibitor-resistant/intolerant Ph+ leukemia given BOS 400 to 600 mg/d with food; and a phase 3 trial of pts with newly diagnosed Ph+ chronic phase chronic myeloid leukemia given BOS 500 mg/d with food. 870 pts contributed to the PK analysis (typically 6–9 PK samples/pt). Pts were aged 18 to 91 y and weighed 35 to 221 kg. The final BOS PPK model was a 2-compartment model with first-order absorption and an absorption lag. PPK parameters were estimated with acceptable precision (see Table). The volume of the peripheral compartment was large with a slow turnover, and time to peak concentration was 5 to 6 h. The estimated alpha half-life was 19 h, with 68% and 32% of area under the curve (AUC) attributable to the alpha and beta half-lives, respectively. Residual unexplained variability was 30% at doses ≤100 mg and 32% at doses >100 mg. Dose-dependency in relative bioavailability (F) was seen, mostly at lower doses. PPK showed high inter-individual variability (IIV), consistent with high variability in BOS absorption. The lower F inferred for low doses could be accounted for by saturable active transport of bosutinib into the gut lumen, which shows more variability than absorption by passive diffusion. Baseline demographics and lab results could not account for the high IIV, and adjusting the BOS dose for body size was not beneficial. Model simulations showed that median AUC and peak concentration (Cmax) at steady-state were 4,322 ng/mL•h and 215 ng/mL, respectively, for BOS 500 mg/d. Within individuals, differences between peak and trough concentrations were relatively small, with a population fluctuation ratio (Cmax/Cmin) of 152%. BOS approached steady-state after 4 days, but concentrations were predicted to rise slowly during maintenance, characteristic of a drug with a large peripheral distribution volume. The model-based accumulation index was 2.45, which is in agreement with the 2- to 3-fold increase inferred from noncompartmental analysis. In conclusion, the PPK model of BOS showed acceptable descriptive and predictive performance, suitable for deriving individual exposure metrics for subsequent pharmacodynamic analyzes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A195.