Daryl Sonnichsen

Effect of Ketoconazole on the Pharmacokinetics of Oral Bosutinib in Healthy Subjects

Bosutinib (SKI‐606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open‐label, randomized, 2‐period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once‐daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of Cmax(bosutinib+ketoconazole)/Cmax(bosutinib alone), AUCT(bosutinib+ketoconazole)/AUCT(bosutinib alone), and AUC(bosutinib+ketoconazole)/AUC(bosutinib alone) were assessed. Compared with bosutinib administered alone, coadministration with ketoconazole increased bosutinib Cmax 5.2‐fold, AUCT 7.6‐fold, and AUC 8.6‐fold. Ketoconazole coadministration decreased the mean apparent clearance of bosutinib approximately 9‐fold and increased the mean (SD) terminal half‐life from 46.2 (16.4) hours to 69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between the 2 treatments. The most common AEs were headache, nausea, and increased blood creatinine. No safety‐related discontinuations or serious AEs occurred. These PK results indicate that bosutinib is susceptible to interaction with potent CYP3A4 inhibitors.

Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations.

Temsirolimus, a highly specific inhibitor of mammalian target of rapamycin (mTOR), is a novel anticancer targeted therapy with a new mechanism of action. The prototype mTOR inhibitor, oral rapamycin, is poorly soluble and undergoes extensive first-pass metabolism, leading to low and potentially variable absorption and exposure. For some tumors, maximizing the bioavailability and dose intensity via intravenous (IV) administration may provide optimal clinical benefit. Temsirolimus is an ester analog of rapamycin that retains its potent intrinsic mTOR inhibitory activity while exhibiting better solubility for IV formulation. In the treatment of advanced renal cell carcinoma, temsirolimus is administered as a 30- to 60-minute IV infusion once weekly at a flat dose of 25 mg. This dosage results in high peak temsirolimus concentrations and limited immunosuppressive activity. Because temsirolimus is active and well tolerated, different dosages and schedules are being explored for other solid and hematologic malignancies, including mantle cell lymphoma. Temsirolimus exhibits a high volume of distribution that, together with IV administration, leads to extensive distribution into peripheral tissues. In addition, significant and protracted exposures are attained with sirolimus (rapamycin), the major equipotent metabolite of temsirolimus. Whereas temsirolimus and sirolimus are both metabolized by cytochrome P450 (CYP) 3A4, drug interaction studies with agents that induce or inhibit CYP3A4 activity indicate that exposure to the sirolimus metabolite is somewhat sensitive to pharmacokinetic (PK) drug interaction. Therefore, temsirolimus dose adjustments are warranted if coadministration cannot be avoided. Despite its complexity, the PK profile of IV temsirolimus is well characterized in cancer patients and provides a strong basis for its future study as a monotherapy or in combination with other anticancer agents.

Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects.

AIM The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor. METHODS This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of C(max) (neratinib+ketoconazole): C(max) (neratinib alone), and AUC(neratinib+ketoconazole): AUC(neratinib alone) were assessed. RESULTS Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib C(max) by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median t(max) was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 lh(-1) to 87.1 lh(-1) and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole). CONCLUSION Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib C(max) by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds.

A randomized, crossover, placebo‐ and moxifloxacin‐controlled study to evaluate the effects of bosutinib (SKI‐606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects

Effects of therapeutic and supratherapeutic concentrations of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, on the corrected QT interval (QTc) in 60 healthy adults were assessed, according to ICH‐E14 guidelines, in this 2‐part, randomized, single‐dose, double‐blind, crossover, placebo‐ and open‐label moxifloxacin‐controlled study. Subjects received placebo, moxifloxacin and bosutinib 500 mg with food (therapeutic) in Part 1. In Part 2, subjects received placebo and bosutinib 500 mg plus ketoconazole (supratherapeutic). ANOVA compared baseline‐adjusted QTc for bosutinib with placebo; and bosutinib plus ketoconazole with placebo plus ketoconazole. Primary endpoint was population‐specific QT correction (QTcN). Secondary endpoints were Bazett QT correction (QTcB), Fridericias formula QT correction (QTcF) and individual QT correction (QTcI). Upper bounds for 90% confidence intervals were <10 msec for the mean change in QTcN from placebo at all postdose time points, suggesting that mean therapeutic exposures (Cmax, 114 ng/mL; AUC, 2,330 ng·h/mL) and mean supratherapeutic exposures (Cmax, 326 ng/mL; AUC, 15,200 ng·h/mL) were not associated with QTc changes. Similar results were obtained for QTcB, QTcF and QTcI. No clinically relevant pharmacokinetic/pharmacodynamic relationship was observed between bosutinib concentrations and QTc. No subjects had QTcB, QTcF, QTcI or QTcN >450 msec or change from baseline >30 msec. In summary, therapeutic and supratherapeutic bosutinib exposures are not associated with QTc prolongation in healthy adults.

Ascending Single-Dose Study of the Safety Profile, Tolerability, and Pharmacokinetics of Bosutinib Coadministered With Ketoconazole to Healthy Adult Subjects

BACKGROUND Bosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of bosutinib, allowing for the study of bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. OBJECTIVE This study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of bosutinib can be achieved with ketoconazole. METHODS This was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days -1 and 1 through 4. RESULTS Forty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18-50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for C(max) and 2980 (802) to 23,000 (4020) ng·h/mL for AUC(0-∞); mean AUC(0-24) and AUC(0-last) ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. C(max) and AUC were linear and dose proportional. Mean C(max) at 600 mg was 2.1-fold higher than the steady-state C(max) previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. CONCLUSIONS Single doses of bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.

Abstract B215: Ascending single‐dose study of safety, tolerability, and pharmacokinetics of bosutinib (SKI‐606) in healthy subjects

Introduction: Bosutinib (SKI‐606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of patients with chronic myelogenous leukemia. An oral dose of 500 mg daily shows evidence of clinical efficacy in patients with Philadelphia chromosome‐positive chronic myelogenous leukemia (Cortes et al. Blood 112:1098, 2008). To support the clinical pharmacology assessment of bosutinib, a single‐ascending‐dose safety and pharmacokinetic (PK) evaluation was performed in healthy subjects. Methods: This was a randomized, double‐blind, placebo‐controlled, single‐ascending dose, sequential‐group study of oral bosutinib in healthy subjects. Subjects were originally to receive doses of 200, 400, 600, 800, 1000 and 1200 mg of bosutinib in the fasting state. However, subjects who received 400 mg bosutinib had multiple adverse events and then 200 mg, 400 mg, 600 mg, and 800 mg bosutinib was administered with food. Each cohort included 6 subjects who received one dose of bosutinib and 2 who received placebo. Plasma samples, collected through 96 h post‐dose, were analyzed by using a liquid chromatography/tandem mass spectrometry assay for bosutinib concentrations. PK analyses were performed using a noncompartmental method and dose linearity was assessed using a power model. Results: A total of 55 subjects (41 bosutinib, 14 placebo) were enrolled (47 males, 8 females, median age [range] 28 [18–50] y, 87%White). Thirty‐three (81%) subjects had adverse events (AEs) after receiving bosutinib. The most common AEs for all subjects receiving bosutinib included diarrhea (39% subjects), nausea (29%), headache (22%), postural dizziness (22%) catheter site‐related reaction and fatigue (10% each). The frequency and severity of gastrointestinal AEs appeared to be dose related. Doses up to 600 (fed) were well tolerated. After administration of single ascending doses of 200–800 mg bosutinib with food, absorption of bosutinib was relatively slow with a median tmax of 6 h, and both Cmax and AUC increased with increasing dose in a linear fashion. The apparent volume of distribution (Vz/F) was large (131–214 L/kg), mean clearance (CL/F) was 2.25–3.81 L/h/kg, and mean half‐life was 32–39 h. Food increased bosutinib exposure (Cmax and AUC) by ∼2‐fold and 1.5‐fold after administration of the 200‐mg and 400‐mg doses, respectively. Conclusions: Bosutinib was generally safe and well tolerated in healthy subjects after administration of single oral doses up to 600 mg (fed). The PK of bosutinib was linear when given with food, and the half‐life supports a once‐daily dosing regimen. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B215.