Clinical Pharmacokinetics and Safety of a 10% Aminolevulinic Acid Hydrochloride Nanoemulsion Gel (BF-200 ALA) in Photodynamic Therapy of Patients Extensively Affected With Actinic Keratosis: Results of 2 Maximal Usage Pharmacokinetic Trials

Abstract

The nanoemulsion-based 10% aminolevulinic acid (ALA) hydrochloride gel BF-200 ALA optimizes epidermal penetration of its active ingredient and is approved for topical photodynamic therapy (PDT) for the treatment of actinic keratosis in the United States and Europe. To characterize systemic absorption from dermal application during PDT, ALA and its key active metabolite protoporphyrin IX (PpIX) were analyzed in 2 maximal usage pharmacokinetic trials (MUsT) in patients severely affected with actinic keratosis. The primary objective of both MUsTs was to assess baseline-adjusted plasma concentration-time curves for ALA and PpIX after a single PDT treatment applying either 2 g (1 tube) of BF-200 ALA on the face (MUsT-1) or applying 6 g (3 tubes) of BF-200 ALA on the face/scalp or body periphery (MUsT-2), to 20 or 60 cm2 , respectively. All PDTs were performed using red light at around 635 nm wavelength. Safety and tolerability were documented along with pharmacokinetics. In both MUsTs, ALA plasma concentrations were transiently increased to a maximum concentration at about 2.5 to 3.3 times above endogenous baseline with time to maximum concentration at ≈3 hours after dosing. Plasma levels subsequently returned to baseline within 10 hours after dosing. Overall baseline-adjusted mean area under the baseline-adjusted plasma concentration-time curve from time zero to the last sampling time point at which the concentration was at or above the lower limit of quantification ranged from 142.8 to 146.2, indicating that a similar, minor fraction of topical ALA is systemically absorbed under both dosing regimens. Systemic PpIX exposure after administration of either dose of BF-200 ALA was equally minimal. Application site skin reactions were treatment area size-related, albeit transient and consistent with the known safety profile of BF-200 ALA.

Trial registration: ClinicalTrials.gov NCT04319159.

Keywords: BF-200 ALA; BF-RhodoLED; aminolevulinic acid; maximal usage pharmacokinetic trial; nanoemulsion; protoporphyrin IX.

Conflict of interest statement

B.N., K.O., B.S., C.Z., and H.L. are or were employed by the sponsoring company, and B.N., K.O., B.S., and H.L. hold either stock or stock options of Biofrontera AG. The remaining authors declare no conflicts of interest.

© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Blood sampling and intervention schedule on treatment day. Blood sampling time points are specified in hours relating to the time point of BF‐200 ALA application. Time point 0 is defined as the start of the application of BF‐200 ALA. (A) MUsT‐1 was designed as a fixed‐sequence trial, comparing placebo and BF‐200 ALA sequentially in the same cohort with an identical intervention protocol. Patients were treated on the face or forehead with 2 g BF‐200 ALA (156 mg ALA) and illuminated after 3 hours of incubation with up to 2 lamps. (B) MUsT‐2 was designed as an open‐label trial, patients were treated on either the face/scalp or body periphery with 6 g BF‐200 ALA (468 mg ALA) and illuminated after 3 hours of incubation with up to 2 lamps. ALA, 5‐aminolevulinic acid; MUsT, maximal usage pharmacokinetic trial.

Figure 2

Baseline‐adjusted concentration vs time profiles for ALA. Plasma concentrations of ALA (ng/mL) are plotted against time (h). (A) Individual baseline corrected ALA plasma concentration–time profiles for patients of the pharmacokinetic set of MUsT‐1 (2 g BF‐200 ALA) (n = 12). (B) Individual baseline corrected ALA plasma concentration–time profiles for patients of the pharmacokinetic set of MUsT‐2 (6 g BF‐200 ALA) treated on the face and scalp (n = 16). (C) Individual baseline corrected ALA plasma concentration–time profiles for patients of the pharmacokinetic set of MUsT‐2 (6 g BF‐200 ALA) treated on the body periphery (n = 16). The solid lines in A‐C depict the respective mean concentration versus time profiles for ALA. (D) Geometric mean (geomean) baseline‐adjusted ALA plasma concentrations of the different analysis groups from both trials against time. MUsT‐1 BF‐200 ALA (green, n = 12), MUsT‐1 placebo (yellow, n = 12), MUsT‐2 BF‐200 ALA overall (gray, overall n = 32), MUsT‐2 BF‐200 ALA face/scalp (blue, n = 16), MUsT‐2 BF‐200 ALA periphery (red, n = 16). ALA, 5‐aminolevulinic acid, c, baseline‐adjusted plasma concentration; MUsT, maximal usage pharmacokinetic trial; PDT, photodynamic therapy.

Figure 3

Unadjusted concentration versus time plots for PpIX. Plasma concentrations of PpIX [ng/mL] are plotted against time [h]. As baseline‐adjustment of PpIX generated an abundance of values

Figure 4

Scatter plot of AUC0‐10h for ALA and PpIX in MUsT‐2. Individual AUC0‐10h were derived from baseline‐adjusted plasma concentrations of ALA and PpIX: Data pairs were plotted to analyze for a relationship between exposure to parent drug (ALA) and its photosensitizing key metabolite (PpIX) in plasma. ALA plasma exposure from BF‐200 ALA appears to be no driver of PpIX in plasma in this study. ALA, 5‐aminolevulinic acid; AUC0‐10h, area under the plasma concentration–time curve from time 0 to 10 hours; MUsT, maximal usage pharmacokinetic trial; PpIX, protoporphyrin IX