LORVIQUA Film-coated tablet Ref.[7603] Active ingredients: Lorlatinib

Absorption

Peak lorlatinib concentrations in plasma are rapidly reached with the median T_max of 1.2 hours following a single 100 mg dose and 2.0 hours following multiple dosing of 100 mg once daily.

After oral administration of lorlatinib tablets, the mean absolute bioavailability is 80.8% (90% CI: 75.7, 86.2) compared to intravenous administration.

Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher exposure compared to fasted conditions. Lorlatinib may be administered with or without food.

At 100 mg once daily, the geometric mean (% coefficient of variation [CV]) peak plasma concentration was 577 (42) ng/mL and the AUC₂₄ was 5,650 (39) ng h/mL in patients with cancer. The geometric mean (% CV) oral clearance was 17.7 (39) L/h.

Distribution

In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin or to α₁-acid glycoprotein.

Biotransformation

In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolised primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5 and UGT1A3.

In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.

Elimination

The plasma half-life of lorlatinib after a single 100 mg dose was 23.6 hours. The estimated lorlatinib effective plasma half-life at steady-state following completion of autoinduction was 14.83 hours. Following oral administration of a 100 mg radiolabelled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in faeces, with overall mean total recovery of 88.6%.

Unchanged lorlatinib was the major component of human plasma and faeces, accounting for 44% and 9.1% of total radioactivity, respectively. Less than 1% of unchanged lorlatinib was detected in urine.

Furthermore, lorlatinib is an inducer via human pregnane-X-receptor (PXR) and the human constitutive androstane receptor (CAR).

Linearity/non-linearity

At single dose, lorlatinib systemic exposure (AUC_inf and C_max) increased in a dose-related manner over the 10 to 200 mg dose range. Few data are available over the 10 to 200 mg dose range; however, no deviation from linearity was observed for AUC_inf and C_max after single dose.

After multiple once daily dose administration, lorlatinib C_max increased dose-proportionally and AUC_tau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily.

Also, at steady-state lorlatinib plasma exposures are lower than those expected from single dose pharmacokinetics, indicative of a net time-dependent auto-induction effect.

Hepatic impairment

As lorlatinib is metabolised in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT >2.5 × ULN, or if due to underlying malignancy, >5.0 × ULN or with total bilirubin >1.5 × ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment. No information is available for patients with moderate or severe hepatic impairment.

Renal impairment

Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Population pharmacokinetic analyses have shown that lorlatinib steady-state plasma exposure and C_max values slightly increase with worsening baseline renal function. Based on a renal impairment study, no starting dose adjustments are recommended for patients with mild or moderate renal impairment [eGFR based on Modification of Diet in Renal Disease Study equation (MDRD)-derived eGFR (in mL/min/1.73 m²) × measured body surface area/1.73 ≥30 mL/min]. In this study, lorlatinib AUC_inf increased by 41% in subjects with severe renal impairment (absolute eGFR <30 mL/min) compared to subjects with normal renal function (absolute eGFR ≥90 mL/min). A reduced dose of lorlatinib is recommended in patients with severe renal impairment, e.g., a once daily oral starting dose of 75 mg (see section 4.2). No information is available for patients on renal dialysis.

Age, gender, race, body weight and phenotype

Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight and phenotypes for CYP3A5 and CYP2C19.

Cardiac electrophysiology

In Study A, 2 patients (0.7%) had absolute Fridericia’s correction QTc (QTcF) values >500 msec and 5 patients (1.8%) had a change in QTcF from baseline >60 msec.

In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. No increases in the mean QTc were observed at the mean observed lorlatinib concentrations in this study.

In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study A, lorlatinib was studied in a population of patients that excluded those with QTc interval >470 msec. In the study population, the maximum mean change from baseline for PR interval was 16.4 msec (2-sided 90% upper CI 19.4 msec) (see sections 4.2, 4.4 and 4.8). Of these, 7 patients had a baseline PR >200 msec. Among the 284 patients with PR interval <200 msec, 14% had PR interval prolongation ≥200 msec after starting lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1.0% of patients.

For those patients who develop PR prolongation, dose modification may be required (see section 4.2).

Repeat-dose toxicity

The main toxicities observed were inflammation across multiple tissues (skin and cervix of rats and lung, trachea, skin, lymph nodes and/or the oral cavity including mandibular bone of dogs; associated with increases in white blood cells, fibrinogen and/or globulin and decreases in albumin) and changes in the pancreas (with increases in amylase and lipase), hepatobiliary system (with increases in liver enzymes), male reproductive system, cardiovascular system, kidneys and gastrointestinal tract, peripheral nerves and the CNS (potential for cognitive functional impairment) at dose equivalent to human clinical exposure at the recommended posology. Changes in blood pressure and heart rate, and QRS complex and PR interval were also observed in animals after acute dosing (approximately 2.6 times the human clinical exposure at 100 mg after a single dose based on C_max). All target organ findings with the exception of hepatic bile duct hyperplasia were partially to fully reversible.

Genotoxicity

Lorlatinib is not mutagenic but is aneugenic in vitro and in vivo with a no observed effect level for aneugenicity approximately 16.5 times human clinical exposure at 100 mg based on AUC.

Carcinogenicity

Carcinogenicity studies have not been conducted with lorlatinib. Reproductive toxicity Seminiferous tubular degeneration and/or atrophy in the testes, and epididymal changes (inflammation and/or vacuolation) were observed in the rat and dog. In the prostate, minimal to mild glandular atrophy was observed in dogs at dose equivalent to human clinical exposure at the recommended posology). The effects on male reproductive organs were partially to fully reversible.

In embryo-foetal toxicity studies, conducted in rats and rabbits, respectively, increased embryolethality and lower foetal body weights and malformations were observed. Foetal morphologic abnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domed head, high arched palate and dilation of ventricles of the brain. The exposure at the lowest doses with embryo-foetal effects in animals was equivalent to the human clinical exposure at 100 mg, based on AUC.