المؤلفون: Chen, Joseph, Bearz, Alessandra, Kim, Dong-Wan, Mamdani, Hirva, Bauman, Jessica, Chiari, Rita, Ou, Sai-Hong Ignatius, Solomon, Benjamin J., Soo, Ross A., Felip, Enriqueta, Shaw, Alice T., Thurm, Holger, Clancy, Jill S., Lee, Kimberly, O’Gorman, Melissa, Tanski, Cherie, Pithavala, Yazdi K.

المساهمون: Pfizer

المصدر: Clinical Pharmacokinetics ; volume 63, issue 2, page 171-182 ; ISSN 0312-5963 1179-1926

مصطلحات موضوعية: Pharmacology (medical), Pharmacology

الإتاحة: https://doi.org/10.1007/s40262-023-01309-4Test

المؤلفون: Chen, Joseph, Bearz, Alessandra, Kim, Dong-Wan, Mamdani, Hirva, Bauman, Jessica, Chiari, Rita, Ou, Sai-Hong Ignatius, Solomon, Benjamin J., Soo, Ross A., Felip, Enriqueta, Shaw, Alice T., Thurm, Holger, Clancy, Jill S., Lee, Kimberly, O'Gorman, Melissa, Tanski, Cherie, Pithavala, Yazdi K.

المصدر: Clinical Pharmacokinetics; Feb2024, Vol. 63 Issue 2, p171-182, 12p

مصطلحات موضوعية: ANAPLASTIC lymphoma kinase, NON-small-cell lung carcinoma, PHARMACOKINETICS, P-glycoprotein, PROTEIN-tyrosine kinase inhibitors, CYTOCHROME P-450

مستخلص: Background and Objective: Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase–positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5′-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. Methods: Thirty-two patients received a single oral dose of a probe drug on Day − 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. Results: Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration–time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. Conclusions: Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. ClinicalTrials.gov: NCT01970865. [ABSTRACT FROM AUTHOR]

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المؤلفون: Ibrahim, Sherry M., Pithavala, Yazdi K., Vourvahis, Manoli, Chen, Joseph

المصدر: Clinical and Translational Science ; volume 15, issue 7, page 1561-1580 ; ISSN 1752-8054 1752-8062

الوصف: Although rifampin drug–drug interaction (DDI) studies are routinely conducted, there have been instances of liver function test (LFT) elevations, warranting further evaluation. A literature review was conducted to identify studies in which combination with rifampin resulted in hepatic events and evaluate any similarities. Over 600 abstracts and manuscripts describing rifampin DDI studies were first evaluated, of which 30 clinical studies reported LFT elevations. Out of these, 11 studies included ritonavir in combination with other drug(s) in the rifampin DDI study. The number of subjects that were discontinued from treatment on these studies ranged from 0 to 71 (0–100% of subjects in each study). The number of subjects hospitalized for adverse events in these studies ranged from 0 to 41 (0–83.67% of subjects in each study). LFT elevations in greater than 50% of subjects were noted during the concomitant administration of rifampin with ritonavir‐boosted protease inhibitors and with lorlatinib; with labeled contraindication due to observed hepatotoxicity related safety findings only for saquinavir/ritonavir and lorlatinib. In the lorlatinib and ritonavir DDI studies, considerable LFT elevations were observed rapidly, typically within 24–72 h following co‐administration. A possible sequence effect has been speculated, where rifampin induction prior to administration of the combination may be associated with increased severity of the LFT elevations. The potential role of rifampin in the metabolic activation of certain drugs into metabolites with hepatic effects needs to be taken into consideration when conducting rifampin DDI studies, particularly those for which the metabolic profiles are not fully elucidated.

الإتاحة: https://doi.org/10.1111/cts.13281Test

المؤلفون: Sun, Steven, Pithavala, Yazdi K., Martini, Jean‐François, Chen, Joseph

المصدر: The Journal of Clinical Pharmacology ; volume 62, issue 9, page 1170-1176 ; ISSN 0091-2700 1552-4604

الوصف: Lorlatinib is a third‐generation, brain‐penetrant anaplastic lymphoma kinase (ALK) and c‐ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with ALK‐ or ROS1‐ positive non‐small cell lung cancer (NSCLC). Data from the ongoing open‐label, single‐arm, multicenter, phase‐1/2 study of lorlatinib in patients with metastatic ALK‐ or ROS1‐ positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10–200 mg once daily or 35–100 mg twice daily) or the approved dosing (100 mg daily). Plasma was collected from all patients, and cerebrospinal fluid (CSF) was collected at baseline and during the study from 5 patients with suspected or confirmed leptomeningeal carcinomatosis or carcinomatous meningitis. For those 5 patients, lorlatinib concentrations ranged from 2.64 to 125 ng/mL in the CSF and from 12.7 to 457 ng/mL in the plasma; free plasma concentrations ranged from 4.318 to 155.385 ng/mL. The CSF/free plasma ratio was 0.77 (R 2 = 0.96 and P < .001). Using a post‐hoc population pharmacokinetic model, the average steady‐state unbound plasma concentration of lorlatinib was derived and the CSF concentration was estimated for all patients. Known minimum efficacy concentrations (C eff ) for wild‐type and mutated (L1196M and G1202R) ALK were used to derive central nervous system (CNS) C eff . Estimated CNS concentrations exceeded the derived CNS C eff values in all patients for wild‐type ALK and the ALK L1196M mutation, and in 35.8% of patients for the ALK G1202R mutation. Projected lorlatinib CNS concentrations were consistent with the high intracranial response rates reported in clinical trials and provide further evidence of the potent CNS penetration of lorlatinib.

الإتاحة: https://doi.org/10.1002/jcph.2056Test

المؤلفون: Hibma, Jennifer E., O’Gorman, Melissa, Nepal, Sunil, Pawlak, Sylvester, Ginman, Katherine, Pithavala, Yazdi K.

المصدر: Cancer Chemotherapy and Pharmacology ; volume 89, issue 6, page 839-839 ; ISSN 0344-5704 1432-0843

مصطلحات موضوعية: Pharmacology (medical), Cancer Research, Pharmacology, Toxicology, Oncology

الإتاحة: https://doi.org/10.1007/s00280-022-04421-7Test

المؤلفون: Lin, Swan, Gong, Jason, Canas, George C., Winkle, Peter, Pelletier, Kathleen, LaBadie, Robert R., Ginman, Katherine, Pithavala, Yazdi K.

المصدر: European Journal of Drug Metabolism and Pharmacokinetics ; volume 47, issue 3, page 441-441 ; ISSN 0378-7966 2107-0180

مصطلحات موضوعية: Pharmacology (medical), Pharmacology

الإتاحة: https://doi.org/10.1007/s13318-022-00759-8Test

المؤلفون: Lin, Swan, Gong, Jason, Canas, George C., Winkle, Peter, Pelletier, Kathleen, LaBadie, Robert R., Ginman, Katherine, Pithavala, Yazdi K.

المساهمون: Pfizer

المصدر: European Journal of Drug Metabolism and Pharmacokinetics ; volume 47, issue 2, page 235-245 ; ISSN 0378-7966 2107-0180

مصطلحات موضوعية: Pharmacology (medical), Pharmacology

الإتاحة: https://doi.org/10.1007/s13318-021-00747-4Test

المؤلفون: Chen, Joseph, Houk, Brett, Pithavala, Yazdi K., Ruiz‐Garcia, Ana

المساهمون: Pfizer

المصدر: CPT: Pharmacometrics & Systems Pharmacology ; volume 10, issue 2, page 148-160 ; ISSN 2163-8306 2163-8306

الوصف: Lorlatinib, a selective inhibitor of anaplastic lymphoma kinase (ALK) and c‐ROS oncogene 1 (ROS1) tyrosine kinase, is indicated for the treatment of ALK‐positive metastatic non‐small cell lung cancer (NSCLC) following progression on crizotinib and at least one other ALK inhibitor, or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease. The population pharmacokinetics (PopPK) of lorlatinib was conducted by nonlinear mixed effects modeling of data from 330 patients with ALK‐positive or ROS1‐positive NSCLC and 95 healthy participants from six phase I studies in healthy volunteers; demographic, metabolizer phenotype, and patient prognostic factors were evaluated as covariates. Lorlatinib plasma PK was well‐characterized by a two‐compartment model with sequential zero‐order and first‐order absorption and a time‐varying induction of clearance. Single dose clearance was estimated to be 9.04 L/h. Assuming that the metabolic auto‐induction of lorlatinib reaches saturation in ~ 5 half‐lives, clearance was estimated to approach a maximum of 14.5 L/h at steady‐state after a period of ~ 7.25 days. The volume of distribution of the central compartment was estimated to be 121 L and the first‐order absorption rate constant was estimated to be 3.1 h −1 . Baseline albumin and lorlatinib total daily dose were significant covariates on lorlatinib clearance. Use of proton pump inhibitors was found to be a significant covariate on the lorlatinib absorption rate constant. These factors were assessed to have no clinically meaningful impact on lorlatinib plasma exposure, and no dose adjustments are considered necessary based on the examined covariates.

الإتاحة: https://doi.org/10.1002/psp4.12585Test

المؤلفون: Xu, Huiping, O'Gorman, Melissa T., Nepal, Sunil, James, Lee P., Ginman, Katherine, Pithavala, Yazdi K.

المصدر: Clinical Pharmacology in Drug Development ; volume 10, issue 11, page 1395-1404 ; ISSN 2160-763X 2160-7648

الوصف: 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.

الإتاحة: https://doi.org/10.1002/cpdd.1000Test

المؤلفون: Hibma, Jennifer E., O’Gorman, Melissa, Nepal, Sunil, Pawlak, Sylvester, Ginman, Katherine, Pithavala, Yazdi K.

المصدر: Cancer Chemotherapy and Pharmacology ; volume 89, issue 1, page 71-81 ; ISSN 0344-5704 1432-0843

مصطلحات موضوعية: Pharmacology (medical), Cancer Research, Pharmacology, Toxicology, Oncology

الوصف: Purpose Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants. Methods Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. Results In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73–86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study. Conclusion Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.

الإتاحة: https://doi.org/10.1007/s00280-021-04368-1Test