Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants.

AIMS: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on 2 separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily for 8 days. Serial blood samples were collected and analysed using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were estimated by using a noncompartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms and laboratory assessments. RESULTS: Twelve participants were enrolled and completed the study. Coadministration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg once daily) increased caffeine exposure compared with caffeine given alone. Area under the curve to infinity and maximum concentration of caffeine increased by approximately 165 and 10%, respectively, when coadministered with ritlecitinib. The ratios of the adjusted geometric means (90% confidence interval) for caffeine area under the curve to infinity and maximum concentration were 265.14% (234.12-300.26%) and 109.74% (103.90-15.91%), respectively, when caffeine was coadministered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when coadministered with a single dose of caffeine were generally safe and well tolerated in healthy participants. CONCLUSION: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3). The sum of potency-adjusted unbound exposures of abrocitinib and its 2 active metabolites is termed the abrocitinib active moiety. We evaluated effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety. METHODS: Three fixed-sequence, open-label, phase I studies in healthy adult volunteers examined the drug-drug interactions (DDIs) of oral abrocitinib with fluvoxamine and fluconazole, rifampin, and probenecid. RESULTS: Co-administration of abrocitinib with fluvoxamine or fluconazole increased the area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of the unbound active moiety of abrocitinib by 91% and 155%, respectively. Co-administration with rifampin decreased the unbound active moiety AUCinf by 56%. The OAT3 inhibitor probenecid increased the AUCinf of the unbound active moiety by 66%. CONCLUSIONS: It is important to consider the effects of DDIs on the abrocitinib active moiety when making dosing recommendations. Co-administration of strong CYP2C19/2C9 inhibitors or CYP inducers impacted exposure to the abrocitinib active moiety. A dose reduction by half is recommended if abrocitinib is co-administered with strong CYP2C19 inhibitors, whereas co-administration with strong CYP2C19/2C9 inducers is not recommended. No dose adjustment is required when abrocitinib is administered with OAT3 inhibitors. CLINICAL TRIALS REGISTRATION IDS: NCT03634345, NCT03637790, NCT03937258.

Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants.

Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.

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 Bioequivalence of Tafamidis 61-mg Free Acid Capsules and Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers.

Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVES: Crizotinib (250 mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings. METHODS: The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib. RESULTS: No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing. CONCLUSIONS: These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily.

Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects.

1. Crizotinib (XALKORI®), an oral inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor kinase (c-Met), is currently approved for the treatment of patients with non-small cell lung cancer that is ALK-positive. 2. The metabolism, excretion and pharmacokinetics of crizotinib were investigated following administration of a single oral dose of 250 mg/100 µCi [(14)C]crizotinib to six healthy male subjects. 3. Mean recovery of [(14)C]crizotinib-related radioactivity in excreta samples was 85% of the dose (63% in feces and 22% in urine). 4. Crizotinib and its metabolite, crizotinib lactam, were the major components circulating in plasma, accounting for 33% and 10%, respectively, of the 0-96 h plasma radioactivity. Unchanged crizotinib was the major excreted component in feces (∼ 53% of the dose). In urine, crizotinib and O-desalkyl crizotinib lactam accounted for ∼ 2% and 5% of the dose, respectively. Collectively, these data indicate that the primary clearance pathway for crizotinib in humans is oxidative metabolism/hepatic elimination. 5. Based on plasma exposure in healthy subjects following a single dose of crizotinib and in vitro potency against ALK and c-Met, the crizotinib lactam diastereomers are not anticipated to contribute significantly to in vivo activity; however, additional assessment in cancer patients is warranted.

A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.

Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2H-pyridazin-3-one, 8l, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable plasma t(1/2) (26 +/- 3 h).

A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one.

We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED(90) values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).

A sorbitol dehydrogenase inhibitor of exceptional in vivo potency with a long duration of action: 1-(R)-[4-[4-(4,6-dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl]ethanol.

We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action.