Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.
In mice subcutaneously implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors, administration of lorlatinib resulted in antitumor activity. Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.
Exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure.
Cardiac Electrophysiology
In 295 patients who received LORBRENA at the recommended dosage of 100 mg once daily and had an ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation ≥200 ms after starting LORBRENA. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1% of patients.
In 275 patients who received LORBRENA at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.
Steady-state lorlatinib maximum plasma concentration (Cmax) increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage). At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0–24h was 5650 ng∙h/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.
Absorption
The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady-state.
The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration.
Distribution
Lorlatinib was 66% bound to plasma proteins at a concentration of 2.4 µM. The blood-to-plasma ratio was 0.99, in vitro. The mean (CV%) steady-state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose.
Elimination
The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of LORBRENA. The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady-state, suggesting autoinduction.
Metabolism
Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3, in vitro.
In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity. The oxidative cleavage metabolite, M8, is pharmacologically inactive.
Specific Populations
No clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment (total bilirubin ≥ 1.5 × ULN with any AST) on lorlatinib pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].
Patients with Severe Renal Impairment
Following administration of a single oral 100 mg dose of LORBRENA, lorlatinib AUCinf increased by 42% in subjects with severe renal impairment (CLcr 15 to <30 mL/min, estimated by Cockcroft-Gault) compared to subjects with normal renal function (CLcr ≥ 90 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of lorlatinib have not been studied in patients with end-stage renal disease requiring hemodialysis.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong CYP3A Inducers on Lorlatinib: Rifampin (a strong CYP3A inducer that also activates PXR) 600 mg once daily for 8 days (Days 1 to 8) coadministered with a single oral 100 mg dose of LORBRENA on Day 8 reduced the mean lorlatinib AUCinf by 85% and Cmax by 76%. Grade 2 to 4 increases in ALT or AST occurred within 3 days. Grade 4 ALT or AST elevations occurred in 50%, Grade 3 ALT or AST elevations in 33%, and Grade 2 ALT or AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within 7 to 34 days (median 15 days) [see Drug Interactions (7.1)].
Effect of Moderate CYP3A Inducers on Lorlatinib: Modafinil (a moderate CYP3A inducer) decreased AUCinf by 23% and decreased Cmax by 22% of a single oral 100 mg dose of LORBRENA [see Drug Interactions (7.1)].
Effect of Strong CYP3A Inhibitors on Lorlatinib: Itraconazole (a strong CYP3A inhibitor) increased AUCinf by 42% and increased Cmax by 24% of a single oral 100 mg dose of LORBRENA [see Drug Interactions (7.1)].
Effect of Fluconazole on Lorlatinib: Fluconazole is predicted to increase steady-state AUCtau and Cmax of lorlatinib by 59%, and 28%, respectively, following concomitant oral administration of 100 mg of LORBRENA once daily and 200 mg fluconazole once daily [see Drug Interactions (7.1)].
Effect of Moderate CYP3A Inhibitors on Lorlatinib: No clinically significant effect on steady-state lorlatinib pharmacokinetics is predicted when used concomitantly with verapamil or erythromycin.
Effect of Lorlatinib on CYP3A Substrates: LORBRENA 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) [see Drug Interactions (7.2)].
Effect of Lorlatinib on CYP2B6 Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 25% and Cmax by 27% of a single oral 100 mg dose of bupropion (a sensitive CYP2B6 substrate).
Effect of Lorlatinib on CYP2C9 Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 43% and Cmax by 15% of a single oral 100 mg dose of tolbutamide (a sensitive CYP2C9 substrate).
Effect of Lorlatinib on UGT1A Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 45% and Cmax by 28% of a single oral 100 mg dose of acetaminophen (a UGT1A substrate).
Effect of Lorlatinib on P-gp Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 67% and Cmax by 63% of a single oral 60 mg dose of fexofenadine (a P-gp substrate) [see Drug Interactions (7.2)].
In Vitro Studies
Effect of Lorlatinib on CYP Enzymes: Lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A and activates PXR, with the net effect in vivo being induction. Lorlatinib induces CYP2B6 and activates the human constitutive androstane receptor (CAR). Lorlatinib and the major circulating metabolite, M8, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. M8 does not inhibit CYP3A.
M8 does not induce CYP1A2, CYP2B6, or CYP3A.
Effects of Lorlatinib on UDP-glucuronosyltransferase (UGT): Lorlatinib and M8 do not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.
Effect of Lorlatinib on Transporter Systems: Lorlatinib is an inhibitor of P-gp and activates PXR (potential to induce P-gp), with the net effect in vivo being induction. Lorlatinib inhibits organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP). Lorlatinib does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OCT2, MATE2K, or systemic BCRP. M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K.
Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.
In mice subcutaneously implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors, administration of lorlatinib resulted in antitumor activity. Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.
Exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure.
Cardiac Electrophysiology
In 295 patients who received LORBRENA at the recommended dosage of 100 mg once daily and had an ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation ≥200 ms after starting LORBRENA. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1% of patients.
In 275 patients who received LORBRENA at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.
Steady-state lorlatinib maximum plasma concentration (Cmax) increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage). At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0–24h was 5650 ng∙h/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.
Absorption
The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady-state.
The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration.
Distribution
Lorlatinib was 66% bound to plasma proteins at a concentration of 2.4 µM. The blood-to-plasma ratio was 0.99, in vitro. The mean (CV%) steady-state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose.
Elimination
The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of LORBRENA. The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady-state, suggesting autoinduction.
Metabolism
Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3, in vitro.
In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity. The oxidative cleavage metabolite, M8, is pharmacologically inactive.
Specific Populations
No clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment (total bilirubin ≥ 1.5 × ULN with any AST) on lorlatinib pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].
Patients with Severe Renal Impairment
Following administration of a single oral 100 mg dose of LORBRENA, lorlatinib AUCinf increased by 42% in subjects with severe renal impairment (CLcr 15 to <30 mL/min, estimated by Cockcroft-Gault) compared to subjects with normal renal function (CLcr ≥ 90 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of lorlatinib have not been studied in patients with end-stage renal disease requiring hemodialysis.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong CYP3A Inducers on Lorlatinib: Rifampin (a strong CYP3A inducer that also activates PXR) 600 mg once daily for 8 days (Days 1 to 8) coadministered with a single oral 100 mg dose of LORBRENA on Day 8 reduced the mean lorlatinib AUCinf by 85% and Cmax by 76%. Grade 2 to 4 increases in ALT or AST occurred within 3 days. Grade 4 ALT or AST elevations occurred in 50%, Grade 3 ALT or AST elevations in 33%, and Grade 2 ALT or AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within 7 to 34 days (median 15 days) [see Drug Interactions (7.1)].
Effect of Moderate CYP3A Inducers on Lorlatinib: Modafinil (a moderate CYP3A inducer) decreased AUCinf by 23% and decreased Cmax by 22% of a single oral 100 mg dose of LORBRENA [see Drug Interactions (7.1)].
Effect of Strong CYP3A Inhibitors on Lorlatinib: Itraconazole (a strong CYP3A inhibitor) increased AUCinf by 42% and increased Cmax by 24% of a single oral 100 mg dose of LORBRENA [see Drug Interactions (7.1)].
Effect of Fluconazole on Lorlatinib: Fluconazole is predicted to increase steady-state AUCtau and Cmax of lorlatinib by 59%, and 28%, respectively, following concomitant oral administration of 100 mg of LORBRENA once daily and 200 mg fluconazole once daily [see Drug Interactions (7.1)].
Effect of Moderate CYP3A Inhibitors on Lorlatinib: No clinically significant effect on steady-state lorlatinib pharmacokinetics is predicted when used concomitantly with verapamil or erythromycin.
Effect of Lorlatinib on CYP3A Substrates: LORBRENA 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) [see Drug Interactions (7.2)].
Effect of Lorlatinib on CYP2B6 Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 25% and Cmax by 27% of a single oral 100 mg dose of bupropion (a sensitive CYP2B6 substrate).
Effect of Lorlatinib on CYP2C9 Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 43% and Cmax by 15% of a single oral 100 mg dose of tolbutamide (a sensitive CYP2C9 substrate).
Effect of Lorlatinib on UGT1A Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 45% and Cmax by 28% of a single oral 100 mg dose of acetaminophen (a UGT1A substrate).
Effect of Lorlatinib on P-gp Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUCinf by 67% and Cmax by 63% of a single oral 60 mg dose of fexofenadine (a P-gp substrate) [see Drug Interactions (7.2)].
In Vitro Studies
Effect of Lorlatinib on CYP Enzymes: Lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A and activates PXR, with the net effect in vivo being induction. Lorlatinib induces CYP2B6 and activates the human constitutive androstane receptor (CAR). Lorlatinib and the major circulating metabolite, M8, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. M8 does not inhibit CYP3A.
M8 does not induce CYP1A2, CYP2B6, or CYP3A.
Effects of Lorlatinib on UDP-glucuronosyltransferase (UGT): Lorlatinib and M8 do not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.
Effect of Lorlatinib on Transporter Systems: Lorlatinib is an inhibitor of P-gp and activates PXR (potential to induce P-gp), with the net effect in vivo being induction. Lorlatinib inhibits organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP). Lorlatinib does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OCT2, MATE2K, or systemic BCRP. M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K.
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