Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics

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 LORVIQUA 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 LORVIQUA . The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1% of patients.

In 275 patients who received LORVIQUA 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.

Pharmacokinetic Properties

12.3 Pharmacokinetics

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.

Effect of Food
There was no clinically significant effect on lorlatinib pharmacokinetics following administration of LORVIQUA with a high fat, high calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat).

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 LORVIQUA . 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.

Excretion
Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged).

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)].


Drug Interaction Studies
Clinical Studies and Model-Informed Approaches

Effect of CYP3A Inducers on Lorlatinib: Twelve healthy subjects received rifampin, a strong CYP3A inducer that also activates PXR, 600 mg once daily for 8 days (Days 1 to 8) and a single oral 100 mg dose of LORVIQUA on Day 8. The coadministration of rifampin with LORVIQUA 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). The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity with the concomitant use of moderate CYP3A inducers is unknown [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 LORVIQUA [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 LORVIQUA 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: LORVIQUA 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: LORVIQUA 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: LORVIQUA 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: LORVIQUA 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: LORVIQUA 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)].

Effect of Acid-Reducing Agents on Lorlatinib: Concomitant use of a proton pump inhibitor, rabeprazole, did not have a clinically significant effect on lorlatinib pharmacokinetics.

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.