Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study.

BACKGROUND: Lorlatinib demonstrated efficacy (including intracranial activity) in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in a phase I/II study (NCT01970865). BACKGROUND AND OBJECTIVE: This analysis describes the pharmacokinetics (PK) of lorlatinib following single and multiple dosing. METHODS: This ongoing, multicenter, open-label, single-arm, phase I/II trial enrolled patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive advanced NSCLC. In phase I, patients received escalating doses of lorlatinib (10-200 mg orally once daily) and twice-daily doses of 35, 75, and 100 mg in continuous 21-day cycles. In phase II, lorlatinib was administered at a starting dose of 100 mg once daily in continuous 21-day cycles. Parameters investigated included the potential for lorlatinib to inhibit/induce cytochrome P450 (CYP) 3A; the absorption/metabolism of lorlatinib and its major metabolite PF-06895751; and differences in these parameters between Asian and non-Asian patients. RESULTS: Data were available for 54 patients from phase I and 275 patients from phase II. Lorlatinib plasma exposure increased dose proportionally after single doses of 10-200 mg, and slightly less than dose proportionally after multiple doses. Lorlatinib clearance increased following multiple dosing compared with single dosing, indicating autoinduction. The area under the concentration-time curve from time zero to time τ (the dosing interval; AUCτ) of PF-06895751 was approximately 80% higher than that of lorlatinib after multiple dosing. Lorlatinib exhibited brain penetration. Furthermore, no overt differences in single- and multiple-dose PK parameters between the Asian and non-Asian patients were observed. CONCLUSIONS: Lorlatinib is highly brain penetrant and exhibits autoinduction after multiple dosing. There appears to be no inherent differences in lorlatinib PK between healthy subjects and cancer patients, or between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865.

The effect of tafamidis on the QTc interval in healthy subjects.

AIMS: The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day(-1) ). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QTc interval in healthy subjects. METHODS: This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra-therapeutic Cmax of ~20 µg ml(-1) ) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of ≥ 14 days. Serial triplicate 12-lead electrocardiograms were performed. QTc intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs). RESULTS: A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QTc F between tafamidis 400 mg and placebo was <10 ms (non-inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin tmax of 3 h post-dose, confirming assay sensitivity. Cmax and AUC(0,24 h) for tafamidis were 20.36 µg ml(-1) and 305.4 µg ml(-1) h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs. CONCLUSIONS: This thorough QTc study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QTc interval and is well-tolerated in healthy volunteers.

Integrating disease progression models, non-clinical pharmacokinetic data and treatment response endpoints to optimize intravitreal dosing regimens.

OBJECTIVE: To rapidly identify patients who will ultimately respond to 1 year of therapy, and optimize their inter dose interval. MATERIALS AND METHODS: An intravitreal (IVT) ophthalmic dosing paradigm was designed based on clinical efficacy, nonclinical pharmacokinetics (PK), and disease progression modeling. Relevant non-clinical PK models were used to extrapolate IVT drug concentrations to patients. RESULTS: Modeling predicted that > 80% of patients who would respond to 1 year of IVT treatment with an improvement in best-corrected visual acuity (BCVA) could be identified after the first 2 doses of treatment. These 2 initial doses produced ~ 75% of the maximum improvement in BCVA attainable. Moreover, the models also predicted those patients who responded after 1 year of treatment may tolerate an extension of the inter dose interval to 12 weeks without significant deterioration of BCVA. In contrast, > 70% of responsive patients who did not respond to 1 year of treatment showed inadequate responses after 2 doses. CONCLUSIONS: These models use data from 2 doses to identify those patients likely to benefit after 1 year of treatment, and thereafter can lengthen their inter dose interval without deleterious effects. This method identifies potential treatment responders early, and lengthens the inter dose interval during long-term administration while allowing non-responders to pursue alternative therapies earlier, thereby minimizing risk to the patient.

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.

Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study).

PURPOSE: To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation. METHODS: This multicenter, prospective, masked, randomized, active-controlled, phase 2 interventional clinical trial enrolled 184 DME patients with best corrected visual acuity (BCVA) of 20/40 to 20/320 inclusive in the study eye. Patients were randomly assigned to 0.4-mg, 1-mg, 3-mg PF-04523655 intravitreal injections or laser. The main outcome measure was the change in BCVA from baseline to month 12. RESULTS: All doses of PF-04523655 improved BCVA from baseline through month 12. At month 12, the PF-04523655 3-mg group showed a trend for greater improvement in BCVA from baseline than laser (respectively 5.77 vs. 2.39 letters; P = 0.08; 2-sided α = 0.10). The study was terminated early at month 12 based on predetermined futility criteria for efficacy and discontinuation rates. PF-04523655 was generally safe and well-tolerated, with few adverse events considered treatment-related. By month 12, the discontinuation rates in the PF-04523655 groups were higher than the laser group and were inversely related to dose levels. CONCLUSIONS: PF-04523655 showed a dose-related tendency for improvement in BCVA in DME patients. Studies of higher doses are planned to determine the optimal efficacious dose of PF-04523655. PF-04523655 may offer a new mode of therapeutic action in the management of DME. (ClinicalTrials.gov number, NCT00701181.).

Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study).

OBJECTIVE: To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects with neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, open-label, prospective, randomized, comparator-controlled exploratory study. PARTICIPANTS: A total of 151 patients with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD who were naive to AMD therapy. METHODS: In this phase 2 study, patients were randomized to 1 of 5 treatment groups with equal ratio. All groups received ranibizumab 0.5 mg at baseline and (a) PF 1 mg every 4 weeks (Q4W) from week 4 to week 12; (b) PF 3 mg Q4W from week 4 to week 12; (c) PF 3 mg every 2 weeks (Q2W) from week 4 to week 12; (d) PF 1 mg + ranibizumab (combination) Q4W from baseline to week 12; and (e) ranibizumab Q4W to week 12. All study treatments were given as intravitreal injections. MAIN OUTCOME MEASURES: The primary end point was the mean change in best-corrected visual acuity (BCVA) from baseline at week 16; secondary end points included the percentage of patients gaining ≥ 10 and ≥ 15 letters in BCVA and mean change in retinal central subfield thickness, lesion thickness, and CNV area. RESULTS: At week 16, the PF 1 mg + ranibizumab combination group achieved numerically greater improvement in mean BCVA from baseline (9.5 letters) than the ranibizumab group (6.8 letters). The difference was not statistically significant. The BCVA improvement in the PF monotherapy groups was less than in the ranibizumab group. Similar trends were observed in the percentage of patients who gained ≥ 10 and ≥ 15 letters. From baseline to week 16 (last observed carried forward), the combination and ranibizumab groups had similar mean reductions in central subfield retinal thickness and total CNV area, which were greater than in all PF monotherapy groups. There were no clinically meaningful differences in reduction of lesion thickness among treatment groups. CONCLUSIONS: In this early, underpowered study evaluating treatments for neovascular AMD, the combination of PF with ranibizumab led to an average gain in BCVA that was more than with ranibizumab monotherapy. No safety concerns 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.

Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects.

The effect of food on the oral bioavailability of sunitinib malate (SU11248, an oral, multi-targeted tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activities) was assessed in a randomized open-label, two-way crossover study. A 50-mg dose of SU11248 was administered to 16 healthy subjects after a 10-h fast in one period and after a high-fat, high-calorie meal in the other period. The 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were within the 80-125% bioequivalence range, indicating the absence of a food effect. SU11248 exposure increased slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, AUC0-last and AUC0-infinity both 112%). There was a delay in the formation/absorption of the active metabolite SU12662 in the fed state (mean Cmax decreased 23%), but exposure remained unaffected (90% CIs for AUC0-last and AUC0-infinity were within 80-125%). These results indicate that SU11248 can be administered with or without food.