Levodopa-carbidopa intestinal gel high concentration formulation is clinically bioequivalent to commercial formulation

Pharmacol Res Perspect. 2019 Apr;7(2):e00473. doi: 10.1002/prp2.473.

Abstract

A new levodopa-carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG-HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG-LV. This study characterizes the LCIG-HV formulation and compares it to the LCIG-LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open-label study was conducted according to a two-period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG-HV formulation was 4% higher than that of the LCIG-LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax , AUCt and AUCinf geometric means for the LCIG-HV formulation were 3%-5% higher than those of the LCIG-LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half-life harmonic mean was 1.6 hour for both formulations. The carbidopa half-life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG-HV and LCIG-LV formulations. Cmax , AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG-LV and LCIG-HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences.

Keywords: bioequivalent; carbidopa; intestinal gel; levodopa.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiparkinson Agents / adverse effects
  • Antiparkinson Agents / blood
  • Antiparkinson Agents / chemistry*
  • Antiparkinson Agents / pharmacokinetics*
  • Carbidopa / adverse effects
  • Carbidopa / blood
  • Carbidopa / chemistry*
  • Carbidopa / pharmacokinetics*
  • Cross-Over Studies
  • Drug Combinations
  • Drug Liberation
  • Female
  • Gels
  • Humans
  • Levodopa / adverse effects
  • Levodopa / blood
  • Levodopa / chemistry*
  • Levodopa / pharmacokinetics*
  • Male
  • Middle Aged
  • Therapeutic Equivalency

Substances

  • Antiparkinson Agents
  • Drug Combinations
  • Gels
  • carbidopa, levodopa drug combination
  • Levodopa
  • Carbidopa