Assessing Pharmacogenomic loci Associated with the Pharmacokinetics of Vamorolone in Boys with Duchenne Muscular Dystrophy

Abstract

Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (T_k0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population T_k0 was 3.14 h yielding an average zero-order absorption rate (k₀) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on T_k0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.

Keywords: Duchenne muscular dystrophy; pharmacogenomics; population pharmacokinetic modeling; vamorolone.

Figure 1.

Plasma vamorolone concentration-time profiles for boys with DMD from VBP15–002 and VBP15–004 studies. Closed circles are individual observations color coded by the indicated doses (unit: mg/kg/day). Lines connect mean values at each dose. Note: 2-mg/kg/day values from the VBP15–004 study are moved from 2 to 1.8 hr for better visualization.

Figure 2.

Individual estimates of clearances (CL/F) and volumes (V/F) versus BW. The solid red line indicates nonlinear regression line applying Eq. 7 with fixed power coefficients of 0.75 for CL/F and 1.0 for V/F.

Figure 3.

Individual plasma concentration versus time plots for boys receiving 2 or 6 mg/kg of vamorolone from the 002 study. Closed circles are observations; solid and dotted lines indicate individual and population predictions by the PopPK model. The data for study day 1 and day 14 are indicated by red and blue.

Figure 4.

Individual estimates of clearances (CL/F) versus genetic covariates. The boxes represent the 25^th to 75^th percentiles, with the whiskers extending to the 5^th and 95^th percentiles of the data and the asterisks representing outliers. The boxes are joined at the median values.