In phase I, a total of 54 patients were treated with lorlatinib: three patients each in the 10, 25, 50, and 150, and 200 mg once-daily cohorts; 12 patients in the 75 mg once-daily cohort; 17 patients in the 100 mg once-daily cohort; three patients in the 35 and 75 mg twice-daily dosing cohorts; and four patients in the 100 mg twice-daily cohort. All treated patients were evaluable and were included in the PK analysis (N = 54). Of these patients, 22 were male and 32 were female; 37 patients were White, 3 were Black, 7 were Asian, 1 was of other ethnicity, and 6 were of unspecified race (Table 1). The mean (SD) age was 51.9 years (12.8), height was 169.0 cm (11.5), and weight was 71.1 kg (18.0). Six patients, three from the 25 mg once-daily cohort and three from the 150 mg once-daily cohort, were enrolled in the midazolam substudy.
In phase II, a total of 275 patients were treated with lorlatinib 100 mg once daily—30, 27, 60, 65, 46, and 47 patients in cohorts EXP-1, EXP-2, EXP-3, EXP-4, EXP-5, and EXP-6, respectively. In addition, three patients were enrolled in the Japan LIC. All treated patients (phase II and the Japan LIC) except one were evaluable for PK assessments and were included in the phase II PK analysis (N = 277). Of these patients, 119 were male and 158 were female; 132 patients were White, 3 were Black, 105 were Asian, 12 were other ethnicities, and 25 were of unspecified race (Table 1). The mean (SD) age was 53.4 years (12.0), height was 166.0 cm (10.5), and weight was 67.6 kg (17.1). Of the 277 patients, 19 had full PK sampling, which allowed for at least one single-dose lorlatinib PK parameter estimation, and 22 had samples allowing for at least one multiple-dose lorlatinib PK parameter estimation.
Single-Dose Lorlatinib PK Results
Median lorlatinib plasma concentration-time profiles following single oral doses of lorlatinib are shown in Fig. 1a and b. Following single doses of 10–200 mg, lorlatinib was absorbed rapidly, with median Tmax values of 1.09–2.00 h, and showed biphasic decline, with a mean plasma t½ of 17.2–27.2 h across all doses. Lorlatinib PK parameter values are summarized descriptively in electronic supplementary Table S1. Lorlatinib dose-normalized exposures did not appear to change across the 10–200 mg dose range (electronic supplementary Fig. S1).
In phase II, lorlatinib was absorbed rapidly, with a median value of 1.15 h following a single dose of 100 mg on Day −7 (Table 2). Following attainment of Cmax, the disposition of lorlatinib declined, with a mean t½ of 23.6 h.
Multiple-Dose Lorlatinib PK Results
Median plasma lorlatinib concentration-time profiles following multiple oral doses in phase I are shown in Fig. 1c and d. Plasma PK parameter values following multiple-dose administration are summarized descriptively in Table 3. On Cycle 1 Day 15 of multiple-dose administration, lorlatinib was absorbed rapidly, with median Tmax values of ≤ 2 h across the entire range of doses, from 10 mg to 200 mg on either once-daily or twice-daily dosing schedules.
Urinary recovery of unchanged lorlatinib following multiple doses was low, with < 0.5% (n = 3) of the dose recovered unchanged in urine for the 100 mg once-daily dosing regimen. Geometric mean renal clearance was 61.3 mL/h. Linear plots of individual and geometric mean dose-normalized AUCτ and Cmax by dose for the once- and twice-daily regimens are shown in Fig. 2.
In general, plasma lorlatinib dose-normalized AUCτ and Cmax slightly decreased across the 10–200 mg once-daily dose range based on visual comparison of individual and geometric mean Cmax and AUCτ values by dose. Arithmetic mean values for the observed Rac, comparing AUCτ for multiple-dose administration with that for single-dose administration, ranged from 1.0 to 1.5 for the once-daily dosing regimen and 1.2 to 2.1 for the twice-daily dosing regimen.
Arithmetic mean values for the Rss, comparing AUCτ for multiple-dose administration with AUC∞ for single-dose administration, were consistently < 1 (ranging from 0.54 to 0.99), suggesting net autoinduction of lorlatinib following multiple oral dosing.
In phase II, on Cycle 1 Day 15 of multiple-dose administration (100 mg once daily), lorlatinib was absorbed rapidly, with a median Tmax value of 1.96 h (Table 2). Lorlatinib plasma concentrations appeared to reach steady state by 15 days with repeated 100 mg once-daily dosing. The Ctrough of lorlatinib across the phase II cohorts and the Japan LIC were fairly consistent, with median values of approximately 100 ng/mL and geometric means (in groups with n ≥3) ranging from 46.4 to 138.5 ng/mL over the period between Cycle 2 Day 1 and Cycle 20 Day 1 (electronic supplementary Table S2). After 100 mg once-daily dosing of lorlatinib, the arithmetic mean value for Rac was 1.08; the arithmetic mean Rss value was 0.66.
An evaluation of the steady-state plasma PK of the most abundant human circulating lorlatinib metabolite, PF-06895751, was performed for 10 patients following repeated 100 mg once-daily administration of lorlatinib. On Cycle 1 Day 15, the PF-06895751 geometric mean AUCτ was 4127 ng·h/mL and the geometric mean Cmax was 193.7 ng/mL, with a median Tmax of 8.1 h. The geometric mean molar ratio for AUCτ of PF-06895751 to lorlatinib was 1.799.
Effect of Lorlatinib on Midazolam PK
Median midazolam plasma concentrations were substantially lowered in the presence of multiple oral doses of lorlatinib (25 mg once daily [n = 3] and 150 mg once daily [n = 3]) compared with those observed when midazolam (2 mg) was administered alone (Fig. 3 and electronic supplementary Table S3). For the 150 mg once-daily cohort, evaluable midazolam PK data were only available for two patients. Midazolam median Tmax was 0.5 h with or without lorlatinib (25 mg once daily and 150 mg once daily). Following attainment of Cmax, the decline in midazolam plasma concentrations was faster when coadministered with lorlatinib; the mean estimate of the midazolam elimination t½ decreased from 5 to 3 h following coadministration with lorlatinib (25 mg once daily). Following the coadministration of midazolam with lorlatinib (25 mg once daily or 150 mg once daily), the midazolam AUC∞ and Cmax values were lower compared with when midazolam was administered alone. The CL/F of midazolam increased from 36.7 and 45.1 L/h when administered alone, to 93.9 and 124.2 L/h when coadministered with lorlatinib 25 mg once daily and 150 mg once daily, respectively. Midazolam AUClast geometric mean values (%CV) decreased from 51.3 (47%) to 20.4 (18%) ng·h/mL and from 36.5 (20%) to 14.4 (25%) ng·h/mL, respectively, with 25 mg once-daily and 150 mg once-daily lorlatinib dosing. Likewise, midazolam Cmax geometric mean values (%CV) decreased from 16.1 (42%) to 9.7 (40%) ng/mL and from 11.6 (48%) to 5.73 (43%) ng/mL, respectively, with 25 mg once-daily and 150 mg once-daily lorlatinib dosing.
Lorlatinib PK Based on Ethnicity
Twelve non-Asian and seven Asian patients (of whom four were Japanese) had single-dose lorlatinib concentration-time data evaluable for PK analysis, and 11 non-Asian and 11 Asian patients (of whom seven were Japanese) had multiple-dose lorlatinib concentration-time data evaluable for PK analysis. Median lorlatinib plasma concentration-time profiles for Asian versus non-Asian patients after single and multiple 100 mg lorlatinib dosing are shown in Fig. 4.
After multiple dosing, on Cycle 1 Day 15, the median peak concentrations of lorlatinib in Asian patients were slightly higher than those in non-Asian patients (644.8 vs. 515.5 ng/mL). Following single-dose lorlatinib administration, a 52% higher lorlatinib Cmax was noted in Asian patients, but changes in AUC were minimal (Table 4). The ratios of the adjusted geometric means (expressed as percentages) for lorlatinib AUC∞ and Cmax (90% confidence interval [CI]) were 110.0% (80.5–150.4%) and 152.4% (116.2–199.9%), respectively, for the Asian population compared with the non-Asian population.
Following multiple dosing, lorlatinib plasma exposure (AUCτ) was similar in Asian and non-Asian patients (Table 4). The ratios of the adjusted geometric means for lorlatinib AUCτ and Cmax (90% CI) Cycle 1 Day 15 were 110.7% (83.7–146.5%) and 125.1% (93.7–166.9%), respectively, for the Asian population compared with the non-Asian population. Similar trends for lorlatinib PK following single and multiple 100 mg once-daily doses were observed in Japanese patients compared with non-Asian patients (data not shown).
The PK parameters of the metabolite PF-06895751 following multiple-dose administration of lorlatinib 100 mg once daily, by ethnicity, are shown in Table 5. The molar PF-06895751 to lorlatinib ratios for AUCτ were similar in the Asian and Japanese populations (1.60 vs. 1.63).
Cerebral Spinal Fluid Results in Phases I and II
Over the course of the study, CSF concentrations and time-matched plasma concentrations of lorlatinib were available for four patients from phase I and one patient from phase II. The CSF concentrations ranged from 2.64 to 125 ng/mL (electronic supplementary Table S3). The mean CSF/free plasma ratio data from phase I was published previously and was reported to be 0.75 . An additional CSF/free plasma ratio measurement from one patient from the phase II portion is reported here and was 0.68.
Lorlatinib Effect on CYP3A as Measured by 4ß-Hydroxycholesterol/Cholesterol and 6ß-Hydroxycortisol/Cortisol Ratios
At the 100 mg once-daily dose of lorlatinib, both 4ß-hydroxycholesterol/cholesterol and 6ß-hydroxycortisol/cortisol ratios reached maximal values by Day 8 of multiple dosing (electronic supplementary Fig. S2).