Biotest’s Pentaglobin® in adults and neonates (term and preterm) – A PBPK approach
Daniel Moj (1), Martin König (1), Matthias Germer (1), Jörg Schüttrumpf (1)
(1) Biotest AG, Germany
Introduction: Pentaglobin® is a polyclonal intravenous immunoglobulin preparation consisting of 12% immunoglobulin M (IgM), 12% immunoglobulin A (IgA), and 76% immunoglobulin G (IgG) that is applied (i) as adjuvant therapy to the treatment of severe bacterial infections and (ii) as immunoglobulin substitution for immunosuppressed patients and during severe secondary antibody deficiency syndrome. So far, no physiologically-based pharmacokinetic model of Pentaglobin® has been developed to virtually assess its pharmacokinetics (PK) following single and multiple doses of Pentaglobin® in adults and neonates (term and preterm).
Objectives: 1. Describe the maturation of IgM, IgA, and IgG for term and preterm neonates.
2. Develop PBPK models to describe and predict the concentration-time profiles of IgM, IgA, and IgG in adults following single and multiple Pentaglobin® doses.
3. Use the maturation data and the developed PBPK models to predict the concentration-time profiles of IgM, IgA, and IgG in term and preterm neonates following various Pentaglobin® dosing schedules.
4. Employ the maturation data and the final PBPK models to assess the Cmax and Ctrough values for IgM, IgA, and IgG following daily doses of 5 mL Pentaglobin®/kg body weight (bw)/day for adults and neonates (term and preterm).
Methods: Maturation data for IgM, IgA, and IgG was gathered from various sources in the literature [e.g. 1-3]. Data for the development of the adult PBPK models for IgM, IgA, and IgG comprised Phase I (age = 32.0 ± 7.13 years, n = 21) and Phase II (age = 70.8 ± 12.0 years, n = 11) with 1492 concentration-time points [4,5]. The data for the evaluation of the predicted neonate concentration curves (no IgA data available) consisted of clinical trial data from 2 internal (n = 11 - 22) and 3 published Pentaglobin® studies (n = 34, gestational age = 28.6 – 31.8 weeks) [6,7]. Adult PBPK models were developed in a step-wise manner in which the available datasets were split into an internal (development) and external (qualification) dataset. IgM, IgA, and IgG maturations were described using Berkeley Madonna 8.3.18. PK-Sim and MoBi (Open Systems Pharmacology Suite 7.3.0) and R 3.5.2 were used for PBPK modelling and simulation. GetData Graph Digitizer version 2.26.0.20 was used to digitize data when necessary.
Results: The maturations of IgM and IgA were best described using a Michaelis-Menten model with baseline parameter, while IgG was best described with an additional linear model (first 3 months after birth). At the date of birth, the typical term (preterm) neonate shows IgM, IgA, and IgG baseline concentrations of 0.13 (0.06), 9.7 (3.6) and 0.04 (0.005) g/L, respectively. The final IgM, IgA, and IgG models described the adult PK data very well and predicted the IgM and IgG PK in neonates successfully with a mean Cmax prediction error (Cmax,pred/Cmax,obs) of 11%. Following multiple doses of 5 mL Pentaglobin®/kg bw/day, model-based simulations suggest a 18% higher baseline-corrected Cmax in neonates in comparison to adults for IgM and IgA, whereas the baseline-corrected IgG Cmax is 31% higher in the neonates. The results for the baseline-corrected Ctrough are comparable.
Conclusions: When developing IgM-, IgA-, or IgG-based drugs for neonates, the maturations of these immunoglobulins must be taken into consideration. The developed PBPK models were able to describe and predict the PK of IgM, IgA, and IgG in adults and neonates, however, in order to evaluate the correctness of the subsequent model-based simulations, more PK data of IgM, IgA, and IgG in neonates is needed. The developed PBPK models my serve as future tools to support the development of IgM-, IgA-, and IgG-based drugs.
References:
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