The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.

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

PURPOSE: Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed. METHODS: Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis. RESULTS: All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142-295%) and 137% (97-193%) in the moderate group, and 202% (146-281%) and 120% (77-188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related. CONCLUSION: The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).

Clinical and Model-Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough QT Study.

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double-blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2-sided 90% confidence intervals (CIs) for all time-matched least-squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure-response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model-derived baseline and placebo-adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5-8.2 milliseconds) and 13.7 milliseconds (12.0-15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20-millisecond threshold of clinical concern in oncology.

Absolute Oral Bioavailability of Glasdegib (PF-04449913), a Smoothened Inhibitor, in Randomized Healthy Volunteers.

Glasdegib (PF-04449913) is an oral small-molecule inhibitor of the Hedgehog signaling pathway under development for treating myeloid malignancies. This was an open-label phase 1, randomized, 2-sequence, 2-treatment, 2-period, crossover study evaluating the absolute bioavailability of glasdegib in healthy volunteers under fasting condition (NCT03270878). In period 1, 12 eligible subjects received either a single oral dose of glasdegib 100 mg (tablet) or a single intravenous (IV) dose of glasdegib 50 mg. Following ≥6-day washout, subjects received the treatment that they did not receive in the first period. Blood samples were collected for up to 96 hours after dosing. Drug plasma concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Glasdegib pharmacokinetic parameters were calculated using noncompartmental analysis. The mean terminal half-life was 14.3 hours for oral tablet treatment vs 13.8 hours for glasdegib IV treatment. The absolute oral bioavailability measured as the ratios (oral/IV) of adjusted geometric mean (90% confidence interval) of dose normalized area under the plasma concentration-time curve was 77.12% (71.83%-82.81%). Two adverse events (1 mild and 1 moderate in severity) were reported by 2 subjects following oral tablet administration; these were fully resolved by the end of the study.

Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma.

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CLt) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymphoma (NHL). Pharmacokinetic data included 8361 InO concentration-time observations that were modeled using nonlinear mixed-effects analysis. Covariate relations were identified using generalized additive modeling on base model parameters and then tested in a stepwise manner via covariate modeling. InO concentration was described with a 2-compartment model with linear and time-dependent clearance components. Based on the final model, baseline body surface area was a covariate of the linear and time-dependent clearance components and volume of distribution in the central compartment; baseline percentage of blasts in the peripheral blood was a covariate of the decay coefficient of the time-dependent clearance term (CLt); and concomitant rituximab treatment was a covariate of the linear clearance component (CL1). The magnitude of change of each pharmacokinetic parameter due to these covariates was not considered clinically relevant. Therefore, no dose adjustment of InO for the treatment of patients with R/R B-cell ALL or NHL is needed on the basis of selected covariates.

Evaluation of the effects of formulation, food, or a proton-pump inhibitor on the pharmacokinetics of glasdegib (PF-04449913) in healthy volunteers: a randomized phase I study.

PURPOSE: To demonstrate the bioequivalence of the planned maleate salt-based commercial glasdegib tablet formulation [International Council for Harmonization (ICH) glasdegib] to the clinical di-hydrochloride (di-HCl) salt-based glasdegib formulation (di-HCl glasdegib). Additionally, to estimate the effects of a high-fat, high-calorie meal and proton-pump inhibitor (PPI) on the pharmacokinetics of ICH glasdegib. METHODS: This Phase I open-label study (ClinicalTrials.gov: NCT03130556) enrolled 24 healthy subjects to receive two different tablet formulations of single-dose 100-mg glasdegib under fasted conditions. A subset of healthy volunteers (n = 12) received single-dose 100-mg ICH glasdegib following a high-fat, high-calorie meal or concurrently with a PPI (rabeprazole). RESULTS: The adjusted geometric mean ratio (ICH glasdegib:di-HCl glasdegib) and 90% confidence intervals (CI) of area under the plasma concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 104.0% (99.7‒108.5%) and 101.6% (96.1‒107.4%), respectively, within the acceptance range for bioequivalence (80‒125%). The adjusted geometric mean ratio (90% CIs) for AUCinf and Cmax under fed conditions were 84.3% (78.6‒90.6%) and 69.0% (61.8‒77.0%), respectively, relative to fasted conditions. When ICH glasdegib was administered concurrently with the PPI, the adjusted geometric mean ratio (90% CI) of AUCinf and Cmax were 100.6% (93.2‒108.6%) and 80.5% (70.7‒91.6%), respectively, relative to fasted conditions. Glasdegib was generally well tolerated under all conditions studied. CONCLUSIONS: The ICH glasdegib tablet formulation was bioequivalent to the clinical di-HCl formulation under fasted conditions. A high-fat, high-calorie meal or concurrent PPI treatment had a minimal effect on glasdegib exposure, and was not considered clinically meaningful.

Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers.

AIMS: This study aimed to evaluate the effect of a strong CYP3A inducer, rifampin, on glasdegib pharmacokinetics in healthy volunteers. METHODS: In an open-label, fixed-sequence, two-period Phase 1 study, subjects received a single 100-mg oral dose of glasdegib alone or following once-daily pre-treatment with 600 mg rifampin. Glasdegib pharmacokinetics were calculated using a noncompartmental analysis. RESULTS: Twelve healthy male volunteers (3 whites, 5 blacks and 4 others) were enrolled in the study. Mean age, weight, height and body mass index was 37.8 years, 83.0 kg, 177.3 cm and 26.5 kg (m2 ) -1 , respectively. When dosed alone, glasdegib geometric mean (% coefficient of variation) area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 8145 ng × h ml-1 (23%) and maximum observed concentration (Cmax ) was 703.2 ng ml-1 (19%). With rifampin, glasdegib AUCinf and Cmax decreased, with an adjusted geometric mean ratio (90% confidence interval) 29.66% (26.17-33.62) for AUCinf and 64.71% (57.21-73.19) for Cmax . Mean terminal half-life decreased from 13.39 to 5.11 hours, geometric mean apparent oral clearance increased from 12.27 to 41.38 l h-1 , whereas median time to Cmax remained similar (1.50 vs. 1.25 hours) in the presence of rifampin. All adverse events (n = 29) were mild in severity and resolved by the end of the study. CONCLUSIONS: Co-administration of rifampin expectedly decreased glasdegib AUCinf and Cmax by ~70% and ~35%, respectively. These results will help to formulate recommendations for dosing strategies in combination with CYP3A inducers in situations where co-administration may be necessary. (clinicaltrials.gov identifier: NCT02430545).

Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers.

PURPOSE: This phase I open-label study investigated the oral bioavailability of two novel maleate salt-based glasdegib (PF-04449913) tablet formulations (small- and large-particle size) relative to the current clinical formulation (diHCl salt-based). In addition, the effect of a gastric pH-altering agent (rabeprazole) and food on the pharmacokinetics of the large-particle size formulation of glasdegib were evaluated. The pharmacokinetics of glasdegib oral solution was also assessed. METHODS: Thirty-four healthy subjects received glasdegib 100 mg as three different formulations in the fasted state (diHCl salt or small- or large-particle size maleate formulation); 13 received the large-particle maleate formulation (fed), and 14 concurrently with rabeprazole (fasted); six subjects received glasdegib 50 mg oral solution (fasted). RESULTS: For both new tablet formulations of glasdegib, ratios (Test:Reference) of adjusted geometric means (90% confidence interval) of area under the concentration-time curve from 0 to infinity and maximum plasma concentration were within 80-125% compared with the diHCl formulation (fasted). For the large-particle size formulation (fed), these ratios were 86.3% (81.0-92.0%) and 75.7% (65.3-87.7%), respectively, compared with fasted. When the large-particle maleate formulation was administered concurrently with rabeprazole versus alone (fasted), these ratios were 111.9% (102.8-121.9%) and 87.2% (75.9-100.3%), respectively. The pharmacokinetics of oral solution was similar to the tablet. CONCLUSIONS: The maleate salt-based tablet formulations were bioequivalent to the diHCl tablet formulation. The extent of the observed effect of a high-fat, high-calorie meal or concurrent rabeprazole treatment on glasdegib exposure is not considered clinically meaningful.

Metabolism, excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration.

1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 µCi [14C]glasdegib to six healthy male volunteers (NCT02110342). 2. The peak concentrations of glasdegib (890.3 ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75 hours post-dose. The AUCinf were 8469 ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity. 3. Mean recovery of [14C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0-120 hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites. 4. Elimination of [14C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.

Pharmacokinetics, metabolism, and excretion of [14C]axitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in humans.

The disposition of a single oral dose of 5 mg (100 µCi) of [(14)C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0-12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%-60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.

Population pharmacokinetic analysis of axitinib in healthy volunteers.

AIMS: Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers. METHODS: Plasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19). RESULTS: A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc ), absorption rate constant (ka ) and absolute bioavailability (F) were 17.0 l h(-1) , 45.3 l, 0.523 h(-1) and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc , but the effect was within the estimated interindividual variability for Vc . CONCLUSIONS: The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted.

Clinical pharmacology of axitinib.

Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that is approved in the US and several other countries for treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy. The recommended clinical starting dose of axitinib is 5 mg twice daily, taken with or without food. Dose increase (up to a maximum of 10 mg twice daily) or reduction is permitted based on individual tolerability. Axitinib pharmacokinetics are dose-proportional within 1-20 mg twice daily, which includes the clinical dose range. Axitinib has a short effective plasma half-life (range 2.5-6.1 h), and the plasma accumulation of axitinib is in agreement with what is expected based on the plasma half-life of the drug. Axitinib is absorbed relatively rapidly, reaching maximum observed plasma concentrations (C max) within 4 h of oral administration. The mean absolute bioavailability of axitinib is 58 %. Axitinib is highly (>99 %) bound to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced renal cell carcinoma, at the 5-mg twice-daily dose in the fed state, the geometric mean (% coefficient of variation) C max and area under the plasma concentration-time curve (AUC) from time 0-24 h (AUC24) were 27.8 ng/mL (79 %) and 265 ng·h/mL (77 %), respectively. Axitinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent (<10 % each), by CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT) 1A1. The two major human plasma metabolites, M12 (sulfoxide product) and M7 (glucuronide product), are considered pharmacologically inactive. Axitinib is eliminated via hepatobiliary excretion with negligible urinary excretion. Although mild hepatic impairment does not affect axitinib plasma exposures compared with subjects with normal hepatic function, there was a 2-fold increase in AUC from time zero to infinity (AUC∞) following a single 5-mg dose in subjects with moderate hepatic impairment. In the presence of ketoconazole, a strong CYP3A4/5 inhibitor, axitinib C max and AUC∞ increased by 1.5- and 2-fold, respectively, whereas co-administration of rifampin, a strong CYP3A4/5 inducer, resulted in a 71 and 79 % decrease in the C max and AUC∞, respectively. Axitinib does not inhibit CYP3A4/5, CYP1A2, CYP2C8, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or UGT1A1 at concentrations obtained with the clinical doses and is not expected to have major interactions with drugs that are metabolized by these enzymes. Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro, but is not expected to inhibit P-gp at therapeutic plasma concentrations. A two-compartment population pharmacokinetic model with first-order absorption and lag time was used to describe axitinib pharmacokinetics. No clinically relevant effects of age, sex, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 inferred phenotype on the clearance of axitinib were identified.

Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers.

PURPOSE: To evaluate the effect of food on axitinib pharmacokinetics in healthy volunteers with two different crystal polymorphs. METHODS: Two separate open-label, randomized, single-dose, three-period, crossover trials were conducted. Study I, conducted first using 5-mg axitinib Form IV film-coated immediate-release (FCIR) tablets, enrolled 18 subjects to compare fed versus fasted states and 24 subjects to evaluate the effect of timing of food consumption on axitinib pharmacokinetics. Study II enrolled 30 subjects to assess the effect of food using 5-mg axitinib Form XLI FCIR tablets. Subjects received axitinib after overnight fasting, with limited fasting or, depending on the study design, after consuming high-fat, high-calorie or moderate-fat, standard-calorie meals. RESULTS: For Form IV FCIR, compared with overnight fasting, axitinib plasma exposure [area under the concentration curve (AUC)] was decreased 23 % when administered with food. For Form XLI FCIR, mean axitinib plasma AUC and maximum plasma concentration (C(max)) were 19 and 11 % higher, respectively, with a high-fat, high-calorie meal compared with overnight fasting. When Form XLI FCIR was administered with moderate-fat, standard-calorie meal, AUC and C(max) were 10 and 16 % lower compared with overnight fasting. Both formulations were well tolerated. Adverse events, mostly gastrointestinal (7 % with Form IV FCIR and 13 % with Form XLI FCIR), were mild to moderate in both studies. CONCLUSIONS: While axitinib Form IV FCIR was associated with higher plasma exposure after overnight fasting, axitinib Form XLI FCIR can be administered with or without food as differences in axitinib pharmacokinetics under the two conditions were not clinically meaningful.

Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers.

OBJECTIVE: Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole. METHODS: In this randomized, single-blind, two-way crossover study, 32 healthy volunteers received placebo, followed by a single 5-mg oral dose of axitinib, administered either alone or on the fourth day of dosing with oral ketoconazole (400 mg/day for 7 days). RESULTS: Axitinib exposure was significantly increased in the presence of ketoconazole, with a geometric mean ratio for area under the plasma concentration-time curve from time zero to infinity of 2.06 (90% confidence interval [CI]: 1.84-2.30) and a geometric mean ratio for maximum plasma concentration (C(max)) of 1.50 (90% CI: 1.33-1.70). For axitinib alone or with ketoconazole, C(max) occurred 1.5 and 2.0 h after dosing, respectively. Adverse events were predominantly mild; the most commonly reported treatment-related adverse events were headache and nausea. CONCLUSIONS: Axitinib plasma exposures and peak concentrations were increased following concurrent administration of axitinib and ketoconazole in healthy volunteers. Axitinib alone and in combination with ketoconazole was well tolerated. These findings provide an upper exposure for expected axitinib plasma concentrations in the presence of potent metabolic inhibition.

Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics.

OBJECTIVE: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment. METHODS: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study. RESULTS: Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported. CONCLUSIONS: Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment.

Pharmacokinetic interaction between amprenavir and delavirdine: evidence of induced clearance by amprenavir.

OBJECTIVE: Our objective was to determine the pharmacokinetic interaction between amprenavir and delavirdine. METHODS: Healthy volunteers participated in 2 open-label, 3-period, longitudinal studies. In the first study, 12 volunteers received a single dose of amprenavir, 1200 mg, alone and then again after 7 days of delavirdine, 600 mg twice daily. In the second study, another 12 subjects received amprenavir, 1200 mg twice daily, alone for 7 days. After a 7-day washout period, subjects received delavirdine, 600 mg twice daily, alone for 7 days followed by a combination with amprenavir, 600 mg twice daily, for another 7 days. Amprenavir and delavirdine pharmacokinetics when given alone and in combination were compared. RESULTS: All 12 subjects completed the first study, and 11 subjects completed the second study. Delavirdine significantly increased the area under the curve (AUC) of single-dose amprenavir by 4-fold (P =.0001). Amprenavir, 600 mg twice daily, with delavirdine produced higher levels of amprenavir AUC, minimum concentration (C(min)), and maximum concentration (C(max)), by 30%, 90%, and 18%, respectively, than those of amprenavir, 1200 mg twice daily, alone (P <.05). In contrast, amprenavir decreased delavirdine AUC, C(min), and C(max) by 50%, 70%, and 30%, respectively (P <.005). CONCLUSIONS: Because of the inhibitory effect of delavirdine on the cytochrome P450 3A4-mediated metabolism of amprenavir, the combination of a reduced dose of amprenavir, 600 mg twice daily, with delavirdine resulted in a higher amprenavir exposure than the standard dose of amprenavir, 1200 mg twice daily. However, amprenavir induced the clearance of delavirdine, resulting in a reduction in delavirdine exposure. Further clinical studies are needed to determine the appropriate dosing regimens for delavirdine and amprenavir during coadministration.