The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants

Patel, Maulik; McGrory, S B; O'Gorman, Melissa; Nepal, Sunil; Ginman, Katherine; Pithavala, Yazdi K.

doi:10.1007/s10637-019-00872-7

Cited by 20 publications

(17 citation statements)

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“…Lorlatinib AUC and C max values in patients with NSCLC in this trial were comparable with those that have been observed in healthy subjects, indicating no inherent differences in PK between healthy subjects and cancer patients [11,12].…”

Section: Discussionsupporting

confidence: 77%

“…In both phase I and phase II, plasma PK parameters, including the maximum plasma concentration ( C max ), time to C max ( T max ), and area under the plasma concentration versus time curve (AUC) for lorlatinib and the metabolite PF-06895751, were determined for both single and multiple doses of lorlatinib. The specific bioanalytical methods used have been previously published [ 11 , 12 ]. Blood samples were collected for serial PK profiling of lorlatinib up to 120 h postdose on Day −7 and up to 24 h postdose on Cycle 1 Day 15, for all phase I patients and a subset of phase II patients.…”

Section: Methodsmentioning

confidence: 99%

“…were determined for both single and multiple doses of lorlatinib. The specific bioanalytical methods used have been previously published [11,12]. Blood samples were collected for serial PK profiling of lorlatinib up to 120 h postdose on Day −7 and up to 24 h postdose on Cycle 1 Day 15, for all phase I patients and a subset of phase II patients.…”

Section: Trial Design and Patientsmentioning

confidence: 99%

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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

et al. 2021

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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; AUC τ ) 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.Lee P. James, Karen J. Klamerus and Ganesh Mugundu at the time this research was conducted.

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Section: Discussionsupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Trial Design and Patientsmentioning

confidence: 99%

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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

et al. 2021

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“…8 Coadministration of lorlatinib with the strong CYP3A inhibitor, itraconazole, increased the plasma exposure of lorlatinib in healthy participants. 9 Lorlatinib was designed to penetrate the bloodbrain barrier, and an in vitro study found that lorlatinib had greater inhibitory effects than crizotinib on immortalized human brain microvascular endothelial cells and also increased brain permeability in rats. [10][11][12][13] In a murine study, it was found that lorlatinib brain accumulation was inhibited by P-glycoprotein, and in another murine model it was shown that simultaneous administration with elacridar, a P-glycoprotein inhibitor, increased absolute brain levels of lorlatinib.…”

Section: Corresponding Authormentioning

confidence: 99%

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

O'Gorman

Nepal

et al. 2021

Clinical Pharm in Drug Dev

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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. Keywordsdrug-drug interactions, drug-food interactions, food effect, lorlatinib, pharmacokinetics and drug metabolism, proton pump inhibitor, rabeprazole Small-molecule tyrosine kinase inhibitors (TKIs) of anaplastic lymphoma kinase (ALK) are used to treat patients with advanced or metastatic non-small cell

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“…But, data from these PBPK simulations are not always available early after approval of a drug. This is for example the case for drugs that are conditionally approved, as is the case for, for instance, larotrectinib, and lorlatinib ( Food and Drug Administration, 2017 ; Food and Drug Administration, 2018 ; Chen et al, 2020 ; Patel et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs

et al. 2021

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Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.

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The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants

Cited by 20 publications

References 2 publications

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

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

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

A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs

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