Population Pharmacokinetics of Brentuximab Vedotin in Adult and Pediatric Patients With Relapsed/Refractory Hematologic Malignancies: Model-Informed Hypothesis Generation for Pediatric Dosing Regimens

Abstract

Prior pharmacokinetic (PK) analyses of the antibody-drug conjugate (ADC) brentuximab vedotin (1.8 mg/kg every 3 weeks) in pediatric patients with relapsed/refractory hematologic malignancies found that patients aged <12 years exhibited decreased ADC area under the curve (AUC) compared with those aged ≥12 years. This population PK (POPPK) analysis used data from pediatric (NCT01492088) and adult (NCT00430846) studies of brentuximab vedotin to quantify body size effects on ADC exposure. Data were collected from 84 patients with a median age of 25.7 years (range, 7.7-87.3 years), 34 of whom (40.5%) were aged <18 years; median patient weight was 67 kg (range, 21-154 kg), and median body surface area was 1.8 m2 (range, 0.87-2.81 m2 ). ADC PK was described by a linear 3-compartment model with zero-order input and first-order elimination. POPPK modeling indicated that dosing brentuximab vedotin at 1.8 mg/kg every 3 weeks or 1.2 mg/kg every 2 weeks resulted in lower ADC AUC values in small/moderate-sized pediatric patients (<28 kg and 28-49 kg, respectively) compared with large pediatric/adult patients (50-100 kg). Dosing at 71.5 mg/m2 every 3 weeks and 47.7 mg/m2 every 2 weeks was predicted to achieve comparable AUC values across all body weight ranges and a similar AUC to that in the 50- to 100-kg group at the standard doses of 1.8 mg/kg every 3 weeks and 1.2 mg/kg every 2 weeks, respectively. These results have generated a hypothesis to support evaluation of brentuximab vedotin at 48 mg/m2 every 2 weeks in combination with adriamycin, vinblastine, and dacarbazine chemotherapy in an ongoing pediatric trial in frontline Hodgkin lymphoma (NCT02979522).

Keywords: oncology; pediatrics; population pharmacokinetics.

Conflict of interest statement

A.S., G.S., and J.K. disclose employment by and D.R.M. is a paid consultant for Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. K.V. discloses previous employment by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and current employment by EMD Serono, Inc. Writing assistance for this article was provided by Rebecca Vickers and Hedley Coppock of FireKite, an Ashfield company, part of UDG Healthcare plc, and was funded by Millennium Pharmaceuticals, Inc. All editorial procedures complied with Good Publication Practice 3 guidelines (Battisti WP, et al. Ann Intern Med. 2015;163:461‐464).

© 2020 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Brentuximab vedotin mechanism of action. Figure reproduced from Suri A, Mould DR, Liu Y, Jang G, Venkatakrishnan K. Population PK and exposure‐response relationships for the antibody‐drug conjugate brentuximab vedotin in CTCL patients in the phase III ALCANZA study. Clin Pharmacol Ther. 2018;104(5)989‐999. ©2018 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. MMAE, monomethyl auristatin E.

Figure 2

Brentuximab vedotin final ADC and MMAE pharmacokinetic model. ADC, antibody‐drug conjugate; ALFM, rate constant to describe the decline in direct conversion of ADC to MMAE following TAD; CLM, apparent MMAE clearance; CLP, ADC clearance; EXP, exponential; FM, fraction metabolized; KD, binding rate constant; Klag, rate constant for lag compartment; MMAE, monomethyl auristatin E; QM, apparent MMAE intercompartmental clearance; QP1 and QP2, ADC intercompartmental clearance from central to first and second peripheral compartments; T‐DTIME, time since last dose; VM and VMP, apparent volume of MMAE central and peripheral compartments; VPc, volume of ADC central compartment; VPp1 and VPp2, volume of ADC first and second peripheral compartments.

Figure 3

Final pharmacokinetic model visual predictive checks for ADC (A, B) and MMAE (C, D) by age group (adult [A, C] or pediatric [B, D]), by time since first dose. For ADC (A, B), observed concentrations are represented by open blue circles. The 95% prediction interval is shown by the dashed black lines, and the 50th percentile is shown as the solid black line. The 95% interval of the observed data is shown by the dashed red lines and the median is shown as the solid red line. The purple‐shaded area is the 95% confidence interval of the 95% prediction interval, and the pink‐shaded area is the 95% confidence interval of the median. For MMAE (C, D), the top panels show the model‐predicted 95% prediction interval (black dashed lines and shaded green area), the observed concentrations (blue circles), and the 95% interval of the observed values (red dashed lines). The lower panels show the observed proportion of BLQ samples (blue lines with blue circles), and the 90% prediction interval of this proportion. ADC, antibody‐drug conjugate; BLQ, below the limit of quantitation; BV, brentuximab vedotin; LLOQ, lower limit of quantitation; MMAE, monomethyl auristatin E.

Figure 4

Simulated ADC AUC by body weight range (A, C, E, G) and concentration‐to‐time profiles (B, D, F, H) following 1.8 mg/kg every‐3‐week dosing (A, B), 71.5 mg/m2 every‐3‐week dosing (C, D), 1.2 mg/kg every‐2‐week dosing (E, F), and 47.7 mg/m2 every‐2‐week dosing (G, H). Each box plot illustrates: the median by the horizontal line in the center, the 25th percentile by the lower end of the box, the 75th percentile by the upper end of the box, the 5th percentile by the lower whisker, and the 95th percentile by the upper whisker. ADC, antibody‐drug conjugate; AUC, area under the concentration‐to‐time curve.

Figure 5

Simulated MMAE AUC by body weight range (A, C, E, G) and concentration‐to‐time profiles (B, D, F, H) following 1.8 mg/kg every‐3‐week dosing (A, B), 71.5 mg/m2 every‐3‐week dosing (C, D), 1.2 mg/kg every‐2‐week dosing (E, F), and 47.7 mg/m2 every‐2‐week dosing (G, H). Each box plot illustrates: the median by the horizontal line in the center, the 25th percentile by the lower end of the box, the 75th percentile by the upper end of the box, the 5th percentile by the lower whisker, and the 95th percentile by the upper whisker. AUC, area under the concentration‐to‐time curve; MMAE, monomethyl auristatin E.