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There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics. The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P‐PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P‐PBPK model (in clinical settings, drug development or to advance pediatric model development in general). Secondary application areas, including dose selection, biologics, and drug interactions, were also assessed. The growth rate for P‐PBPK modeling increased 33‐fold between 2005 and 2020; this was mainly attributed to growth in clinical and drug development applications. For primary applications, 50% of articles were classified under clinical, 18% under drug development, and 33% under model development. The most common secondary applications were dose selection (75% drug development), pharmacokinetic prediction and covariate identification (47% clinical), and model parameter identification (68% model development), respectively. Although population PK modeling remains the mainstay of approaches supporting pediatric drug development, the data presented here demonstrate the widespread application of P‐PBPK models in both drug development and clinical settings. Although applications for pharmacokinetic and drug–drug interaction predictions in pediatrics is advocated, this approach remains underused in areas such as assessment of pediatric formulations, toxicology, and trial design. The increasing number of publications supporting the development and refinement of the pediatric model parameters can only serve to enhance optimal use of P‐PBPK models.

Pediatric physiologically‐based pharmacokinetic (P‐PBPK) models have been used to predict age related changes in the pharmacokinetics (PKs) of renally cleared drugs mainly in relation to changes in glomerular filtration rate. With emerging data on ontogeny of renal transporters, mechanistic models of renal clearance accounting for the role of active and passive secretion should be developed and evaluated. Data on age‐related physiological changes and ontogeny of renal transporters were applied into a mechanistic kidney within a P‐PBPK model. Plasma concentration–time profile and PK parameters of cimetidine, ciprofloxacin, metformin, tenofovir, and zidovudine were predicted in subjects aged 1 day to 18 years. The predicted and observed plasma concentration–time profiles and PK parameters were compared. The predicted concentration–time profile means and 5th and 95th percent intervals generally captured the observed data and variability in various studies. Overall, based on drugs and age bands, predicted to observed clearance were all within two‐fold and in 11 of 16 cases within 1.5‐fold. Predicted to observed area under the curve (AUC) and maximum plasma concentration (Cmax) were within two‐fold in 12 of 14 and 12 of 15 cases, respectively. Predictions in neonates and early infants (up to 14 weeks postnatal age) were reasonable with 15–20 predicted PK parameters within two‐fold of the observed. ciprofloxacin but not zidovudine PK predictions were sensitive to basal kidney uptake transporter ontogeny. The results indicate that a mechanistic kidney model accounting for physiology and ontogeny of renal processes and transporters can predict the PK of renally excreted drugs in children. Further data especially in neonates are required to verify the model and ontogeny profiles.

Pediatric physiologically‐based pharmacokinetic (PBPK) models have broad application in the drug development process and are being used not only to project doses for clinical trials but increasingly to replace clinical studies. However, the approach has yet to become fully integrated in regulatory submissions. Emerging data support an expanded integration of the PBPK model informed approach in regulatory guidance on pediatrics. Best practice standards are presented for further development through interaction among regulators, industry, and model providers.

Imatinib is mainly metabolised by CYP3A4 and CYP2C8 and is extensively bound to α-acid glycoprotein (AAG). A physiologically based pharmacokinetic (PBPK) model for imatinib describing the CYP3A4-mediated autoinhibition during multiple dosing in gastrointestinal stromal tumor patients with normal renal function was previously reported. After performing additional verification, the PBPK model was applied to predict the exposure of imatinib after multiple dosing in cancer patients with varying degrees of renal impairment. In agreement with the clinical data, there was a positive correlation between AAG levels and imatinib exposure. A notable finding was that for recovery of the observed data in cancer patients with moderate RI (CrCL 20 to 39 mL/min), reductions of hepatic CYP3A4 and CYP2C8 abundances, which reflect the effects of RI, had to be included in the simulations. This was not the case for mild RI (CrCL 40 to 50 mL/min). The results support the finding of the clinical study, which demonstrated that both AAG levels and the degree of renal impairment are key components that contribute to the interpatient variability associated with imatinib exposure. As indicated in the 2020 FDA draft RI guidance, PBPK modelling could be used to support an expanded inclusion of patients with RI in clinical studies.

An evolutionary algorithm predicts anti-inflammatory drug combinations that have synergistic effects on IL-1β expression more efficiently than would empirical approaches of testing drug combinations individually. The control of biochemical fluxes is distributed, and to perturb complex intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations leads to a combinatorial explosion in the number of experiments that would have to be performed in a complete analysis. We used a multiobjective evolutionary algorithm to optimize reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-1β expression. The evolutionary algorithm converged on excellent solutions within 11 generations, during which we studied just 550 combinations out of the potential search space of ∼9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the evolutionary algorithm were then optimized pairwise. A p38 MAPK inhibitor together with either an inhibitor of IκB kinase or a chelator of poorly liganded iron yielded synergistic inhibition of macrophage IL-1β expression. Evolutionary searches provide a powerful and general approach to the discovery of new combinations of pharmacological agents with therapeutic indices potentially greater than those of single drugs.

[...]as the immune status of a patient or comedications change, a drug that had not appeared immunogenic for many years of treatment could begin to induce an immune response. [...]a marketed drug may exhibit IG for the first time in a new and sensitive target population, such as patients with an autoimmune disease or children. [...]bioinformatic approaches provide a good basis for screening and optimizing compounds, but they cannot be used to manage IG once a protein therapeutic has entered human trials. The most frequent application of PBPK is the prediction of DDIs and the confidence in this approach is such that regulators accept simulations as a substitute for clinical trials and as the basis for label statements. [...]although DDIs still cannot be “engineered out” completely, they can be predicted and managed effectively through virtual trial simulation using models with sufficient mechanistic detail. The QSP model used in the IG Simulator has sufficient mechanistic detail to integrate diverse inputs, including bioinformatics predictions of MHC II binding to antigenic peptides, in vitro cell‐based assays and clinical measurements of compound concentrations, and ADA titers. [...]a detailed simulation of complex immune system interactions allows for

As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward ( I K1 ) and slow delayed ( I Ks ) rectifier cardiac K + currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of I K1 with BaCl 2 , (ii) selective block of I Ks with (−) chromanol 293B under basal conditions and (iii) selective block of I Ks during β ‐adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl 2 (10  μ M ) was comparable in fibres from female and male dogs. At the same stimulation rates, 10  μ M (−) chromanol 293B did not change the APD in fibres from female and male dogs. During β ‐adrenoceptor stimulation with 0.1  μ M isoproterenol, an APD prolonging effect of (−) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (−) chromanol 293B. In conclusion, our findings confirm that β ‐adrenoceptor stimulation is one condition where there may be an increased role of I Ks in action potential repolarisation. Gender differences in the autonomic modulation of I Ks could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias. British Journal of Pharmacology (2006) 147 , 653–660. doi: 10.1038/sj.bjp.0706491

Women are more prone to develop torsades de pointes, a rare life‐threatening polymorphic ventricular tachycardia, than are men during administration of medicines that have the potential to block IKr (rapid delayed rectifier cardiac K+ current) and to prolong the QT interval. Blockade of IKr, hypokalaemia and extreme bradycardia were used to evaluate whether there are gender differences in cardiac repolarisation in canine Purkinje fibres (PFs). Microelectrode techniques were employed to measure action potential (AP) parameters in PFs from adult female and male dogs. Under control conditions, fibres from female animals in normal or low K+ conditions exhibited significantly longer AP durations at 50% (APD50) and 90% (APD90) of repolarisation as compared with APDs of fibres from male animals. Gender‐related difference to rate adaptation was also present in APD90 of fibres from female animals compared to males. At a stimulation rate of 0.2 Hz, but not at 1.0 Hz, dofetilide elicited a significantly higher increase in APD90, incidence of early afterdepolarisations, triggered and sustained‐triggered activities (TAs) in fibres from female animals compared to males in either normal or low K+ conditions. The sustained TAs were reversed by raising the concentration of [K+]0 in Purkinje preparations from both male (one out of one) and female (12 out of 12) dogs. In conclusion, our data provide experimental evidence pointing to gender differences in canine AP repolarisation. PFs from female dogs can be used in safety pharmacology studies as a sensitive model for evaluating the potential proarrhythmic events in vitro of a new medicinal product. British Journal of Pharmacology (2004) 142, 1255–1264. doi:10.1038/sj.bjp.0705880

As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward (I(K1)) and slow delayed (I(Ks)) rectifier cardiac K(+) currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of I(K1) with BaCl(2), (ii) selective block of I(Ks) with (-) chromanol 293B under basal conditions and (iii) selective block of I(Ks) during beta-adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl(2) (10 microM) was comparable in fibres from female and male dogs. At the same stimulation rates, 10 microM (-) chromanol 293B did not change the APD in fibres from female and male dogs. During beta-adrenoceptor stimulation with 0.1 microM isoproterenol, an APD prolonging effect of (-) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (-) chromanol 293B. In conclusion, our findings confirm that beta-adrenoceptor stimulation is one condition where there may be an increased role of I(Ks) in action potential repolarisation. Gender differences in the autonomic modulation of I(Ks) could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias.

As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward (IK1) and slow delayed (IKs) rectifier cardiac K+ currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of IK1 with BaCl2, (ii) selective block of IKs with (−) chromanol 293B under basal conditions and (iii) selective block of IKs during β‐adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl2 (10 μM) was comparable in fibres from female and male dogs. At the same stimulation rates, 10 μM (−) chromanol 293B did not change the APD in fibres from female and male dogs. During β‐adrenoceptor stimulation with 0.1 μM isoproterenol, an APD prolonging effect of (−) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (−) chromanol 293B. In conclusion, our findings confirm that β‐adrenoceptor stimulation is one condition where there may be an increased role of IKs in action potential repolarisation. Gender differences in the autonomic modulation of IKs could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias. British Journal of Pharmacology (2006) 147, 653–660. doi:10.1038/sj.bjp.0706491