(M-113) Characterization of PK Characteristics of IMMUNORHO after Intramuscular Administration for the Prevention of RhD Isoimmunisation in Rh(D) Negative Women Pregnant with Rh(D) Positive Fetuses: Population Pharmacokinetic Approach

Luisa Rojas – Parexel International; Marta Valle – Parexel International; Anna Lotti Suffredini – Kedrion S.p.A; Miranda Norton – Kedrion S.p.A

Objectives: During a Phase 3 trial sparse blood samples were collected to determine anti-D immunoglobulin serum concentrations in Rh(D) negative women pregnant with Rh(D) positive fetuses following intramuscular administration of 300 µg IMMUNORHO at 28 weeks gestation. The aim was to develop a population pharmacokinetic (popPK) model characterizing the pharmacokinetics (PK) of the anti-D immunoglobulin after the administration of IMMUNORHO to identify covariates affecting anti-D immunoglobulin PK, quantify the magnitude of the effect, and to generate subject-specific PK profiles to estimate anti-D immunoglobulin exposure metrics.

Methods: A graphical analysis of the serum concentration-time data for anti-D immunoglobulin was conducted. The popPK models were developed following an iterative model building process using NONMEM®, version 7.3. Covariate analysis including the effect of baseline body weight, and body mass index (BMI), and white blood cell count was conducted.
The final popPK model for anti-D immunoglobulin was determined based on a range of statistical and graphical assessments. Prediction-corrected visual predictive checks (pcVPCs) were created to evaluate if the final model adequately described the median trend and between subject variability (BSV) in time profiles. The final popPK model was used to simulate individual PK-profiles for each subject evaluable within the popPK analysis dataset and to calculate individual anti-D immunoglobulin PK parameters (Cmax, tmax, AUC0-inf, t1/2, CL/F, V/F) using non-compartmental methods.

Results: A total of 208 serum concentrations from 62 women after receiving a single dose of IMMUNORHO at week 28 of pregnancy, were available for model development. Anti-D immunoglobulin serum concentrations were best described by a one-compartment PK model with first-order absorption and first-order elimination. The PK parameters were estimated to be 0.425 L/day for CL/F, 14.8 L for V/F, and 0.371 1/day for ka. Random effects to describe the BSV in the ka, CL/F and V/F, and a proportional residual error model to describe the residual unexplained variability were integrated into the model. Moderate BSV was observed for all PK parameters (28.1% BSV for CL/F, 39.5% BSV for V/F, 41.4% BSV for ka). CL/F, V/F and ka were allometric scaled by BMI. Dependence between CL/F and V/F random effects was introduced into the model. The pcVPC adequacy of the final popPK model confirmed the predictive performance of the model.
Based on simulation results and using a noncompartmental approach an arithmetic mean CL/F of 0.48 L/day and an arithmetic mean V/F of 17 L were calculated following a single administration of 300 µg immunoglobulin. These parameters exhibited moderate variability. The arithmetic mean t1/2 was approximately 24 days (range 17 to 35 days). The Cmax was 18.08 ng/mL (CV 47.37%), occurring at a median tmax of 7 days (range 4 to 14 days). The overall exposure, measured as AUC0-inf, was 755.64 ng*day/mL (CV 40.38%).

Conclusions: The popPK model successfully characterized the PK profile of pregnant women receiving anti-D immunoglobulin using sparse sampling data, demonstrating the advantage of popPK modeling to efficiently analyze scenarios with limited data collection.

Citations: 1. Clinical Study Protocol KB065. Phase III, Open-label, Uncontrolled, Multicentre Study to Assess Efficacy, Pharmacokinetics and Safety of IMMUNORHO in the Prevention of RhD Isoimmunisation in Rh(D) negative Women Pregnant with Rh(D) positive Foetuses. Version N. 05 of 27/Jul/2022. Amendment 3.
2. Bichler J, Schöndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in pregnant RhD-negative women. BJOG. 2003;110:39-45.
3. Rhophylac Rh0(D) Immune Globulin Intravenous (Human). [package insert] Bern, Switzerland: CSL Behring AG; 2020. https://labeling.cslbehring.com/PI/US/Rhophylac/EN/Rhophylac-Prescribing-Information.pdf
4. Rho(D) Immune Globulin (Human) RhoGAM® Ultra-Filtered PLUS (300 µg) (1500 IU) MICRhoGAM® Ultra-Filtered PLUS (50 µg) (250 IU) Rx Only For Intramuscular Injection Only. Prescribing information Kedrion Biopharma [Accessed September 18, 2024]. https://www.rhogam.com/pdfs/RhoGAM%20Prescribing%20Information.pdf
5. Tiblad E, Wikman A, Rane A, Jansson Y, Westgren M. Pharmacokinetics of 250 μg anti-D IgG in the third trimester of pregnancy: an observational study. Acta Obstet Gynecol Scand 2012;91:587–592.
6. Clinical study report. Evaluation of pharmacokinetics of Kedrion intramuscular anti (D) immunoglobulin. An open label, non-controlled, non-randomized, phase I study on Rh(D) negative healthy volunteers. Final Report of 27/Oct/2006.

Keywords: Population Pharmacokinetic, anti-D immunoglobulin, pregnancy