Disease modelling of repeated acute attacks in an acute intermittent porphyria mouse model
Diego Vera-Yunca (1, 2), Irantzu Serrano-Mendioroz (3), Iñaki F. Trocóniz (1, 2), Antonio Fontanellas (3), Zinnia P. Parra-Guillén (1, 2)
(1) Pharmacometrics & Systems Pharmacology; Department of Pharmacy and Pharmaceutical Technology; School of Pharmacy and Nutrition; University of Navarra, Pamplona, Spain. (2) IdiSNA, Navarra Institute for Health Research; Pamplona, Spain. (3) Hepatology Program, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
Objectives: Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder caused by deficient hepatic activity of the porphobilinogen deaminase enzyme (PBGD), the third enzyme in the haem biosynthesis pathway. Precipitating factors such as porphyrinogenic drugs, hormonal changes, fasting, infections, stress, or alcohol intake increase hepatic demand, leading to acute attacks associated to the accumulation of the neurotoxins ALA and PBG [1]. Compound heterozygote T1/T2 mice (AIP mice) exhibit 33% of normal PBGD activity in the liver. In order to biochemically mimic a human porphyric attack, porphyrinogenic drugs are administered to porphyric animals [2]. The aim of this work was to develop a mechanistic disease model to characterise urinary excreted levels of haem precursors (ALA, PBG and porphyrins) during acute attacks in porphyric mice. This model can be used as a platform to explore the impact of different porphyric treatments and guide dose selection.
Methods: Acute attacks were induced at day 1, 9 and 30 in male AIP mice by intraperitoneal injection of four increasing doses of phenobarbital (75, 80, 85 and 90 mg/kg) every 24 hours. Mice (n=12) were housed in metabolic cages in order to collect 24-hour urine, where haem precursors were quantified. A total of 151 ALA, 154 PBG and 149 porphyrin measurements were available for the analysis. Phenobarbital concentrations were not available for the study. Therefore, plasma phenobarbital concentration (CPheno) profiles were generated using a one compartment model adapted from the literature [3]. It was assumed that phenobarbital was completely and instantly absorbed after an intraperitoneal administration. Data was analysed using the population approach with NONMEM 7.3 software.
Results: Amounts excreted in urine were assumed proportional to (unmeasured) circulating levels of haem precursors with arbitrary values of 1 under unperturbed conditions. In our model, circulating levels of ALA and PBG were considered the precursors of circulating PBG and porphyrins, respectively, with synthesis and degradation rates governed by the KMOD parameter. Phenobarbital increased the synthesis rates of ALA and PBG linearly with respect to CPheno. Maximum CPheno levels of 115.23 mg/L exerted a three-fold increase of KMOD with respect to the estimate at baseline (0.0747 h-1). Inter-animal variability (IAV) was found relevant on the synthesis rate constant for urinary ALA and urinary porphyrins (IAV of 15.5% and 21.7%, respectively). Overall, the final model showed a good parameter precision (RSE <30%) and it was able to satisfactory describe the mean tendency and dispersion of the data as confirmed from the visual predictive checks.
Conclusions: A semi-mechanistic pharmacokinetic-pharmacodynamic disease model for acute intermittent porphyria successfully describing the temporal evolution of the haem precursors excreted in urine after repeated phenobarbital-induced acute attacks has been developed. To the best of our knowledge, this model represents the first computational approach to characterise AIP symptoms in porphyric mice. Moreover, it provides a quantitative framework to explore the impact of new therapies for acute intermittent porphyria and to model their effects in restoring haem precursor synthesis.
References:
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[2] Lindberg RLP, Porcher C, Grandchamp B, Ledermann B, Buerki K, Brandner S, et al. Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria. Nat Genet VO - 12. 1996;(2):195.
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