During the past decades significant progress has been made in our understanding of the importance of age-appropriate development of new drug therapies in children. Importantly, several regulatory initiatives in Europe and the US have provided a framework for a rationale. In the US, most notably the enactment of the Best Pharmaceuticals for Children Act (BPCA) and Product Research and Equity Act (PREA) has facilitated the studying of on-patent and off-patent drugs in children. The biggest challenge in pediatric studies is defining a safe and effective dose or dose range in a patient population that can span from premature neonates to adolescents. From a mechanism-based perspective, advances in the science of quantitative pharmacology and pharmacometrics have resulted in the development of model-based approaches to better describe and understand important age-related factors influencing drug disposition and response in pediatric patients. The application of modeling and simulation has been shown to result in better estimates of pediatric doses as evidenced by several studies, although the optimal approach is still being debated. The extrapolation of efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children. However, a focus on developmental changes in neonates and infants as well as further developing a paradigm for conducting pharmacodynamic studies in neonates, infants, and children remain important unmet needs. In this overview we will review current approaches for age-appropriate dose selection and highlight ongoing efforts to define exposure-response and clinical outcome relationships across the pediatric age spectrum.

1-Aminobenzotriazole (ABT) is widely used as a non-specific inhibitor of animal cytochrome P450 (CYP). In the present study, the inhibitory effect of ABT was investigated on drug oxidations catalyzed by human CYP isoforms. This inhibitory effect was compared with that of SKF-525A, another non-specific inhibitor, and ketoconazole, a potent inhibitor of CYP3A. Bacurovirus-expressed recombinant human CYP isoforms were used as an enzyme source. The specific activities for human CYP isoforms are: phenacetin O-deethylation, for CYP1A2; diclofenac 4'-hydroxylation, for CYP2C9; S-mephenytoin 4'-hydroxylation, for CYP2C19; bufuralol 1'-hydroxylation, for CYP2D6; chlorzoxazone 6-hydroxylation, for CYP2E1; testosterone 6beta-hydroxylation, nifedipine oxidation, and midazolam 1'-hydroxylation, for CYP3A4. ABT inhibited both CYP1A2-dependent activity (Ki=330 microM) and CYP2E1-dependent activity (Ki=8.7 microM). In contrast, SKF-525A weakly inhibited CYP1A2-dependent activities (46% inhibition at 1200 microM) and CYP2E1-dependent activities (65% inhibition at 1000 microM). ABT exhibited the highest Ki value for CYP2C9-dependent diclofenac 4'-hydroxylation among those determined by this assay (Ki=3500 microM). Moreover, SKF-525A showed strong inhibition of CYP2D6-dependent bufuralol 1'-hydroxylation (Ki=0.043 microM). Ketoconazole inhibited all tested drug oxidations, however, its inhibitory effect on CYP1A2-dependent activities was very weak (50% inhibition at 120 microM). ABT, SKF-525A, and ketoconazole showed different selectivity and had a wide range of Ki values for the drug oxidations catalyzed by human CYP enzymes. Therefore, we conclude that inhibitory studies designed to predict the contribution of CYP enzymes to the metabolism of certain compounds should be performed using multiple CYP inhibitors, such as ABT, SKF-525A, and ketoconazole.

This study identified age-appropriate sirolimus dosing regimens for neonates and infants. The algorithm in combination with therapeutic drug management will facilitate sirolimus precision dosing in young children with vascular anomalies. A prospective evaluation is being planned.

Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) and is increasingly being used in transplantation and cancer therapies. Sirolimus has low oral bioavailability and exhibits large pharmacokinetic variability. The underlying mechanisms for this variability have not been explored to a large extent. Sirolimus metabolism was characterized by in vitro intrinsic clearance estimation. Pathway contribution ranked from CYP3A4 > CYP3A5 > CYP2C8. With the well stirred and Qgut models sirolimus bioavailability was predicted at 15%. Interindividual differences in bioavailability could be attributed to variable intestinal CYP3A expression. The physiologically-based pharmacokinetics (PBPK) model developed in Simcyp predicted a high distribution of sirolimus into adipose tissue and another elimination pathway in addition to CYP-mediated metabolism. PBPK model predictive performance was acceptable with Cmax and area under the curve (AUC) estimates within 20% of observed data in a dose escalation study. The model also showed potential to assess the impact of hepatic impairment and drug–drug interaction (DDI) on sirolimus pharmacokinetics.

No abstract

Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration‐time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age‐related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug‐drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3‐fold increase in dose‐normalized tacrolimus concentrations while receiving 2000‐2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA‐approved CBD product. Larger studies are needed to better understand the impact of this drug‐drug interaction in solid organ transplant recipients.

1. Cytochrome P450 (P450, CYP) enzymes involved in drug oxidations in mouse intestines were characterized for their role in the first-pass metabolism of xenobiotics. 2. Preparation of mouse intestinal microsomes using a buffer containing glycerol and protease inhibitors including (p-amidinophenyl) methanesulphonyl fluoride, EDTA, soybean trypsin inhibitor, aprotinin, bestatin and leupeptine gave the highest testosterone 6beta-hydroxylase activity among several preparation buffers tested in this study. Testosterone 6beta-hydroxylase activity catalysed by mouse intestinal microsomes subjected to freezing and thawing was lower than that catalysed by unfrozen intestinal microsomes. 3. Low but significant catalytic activities of nifedipine oxidation, midazolam 1'- and 4-hydroxylation, chlorzoxazone 6-hydroxylation, bufuralol 1'- and 6-hydroxylations and tolbutamide methylhydroxylation were observed in mouse intestinal microsomes. Testosterone 6beta-hydroxylation, chlorzoxazone 6-hydroxylation, and bufuralol 1'- and 6-hydroxylations were inhibited by ketoconazole, diethyldithiocarbamate and quinine respectively. 4. Immunoblot analysis using anti-rat CYP3A antibodies demonstrated two immunoreactive bands showing similar migration in mouse intestinal and hepatic microsomes, although studies using anti-CYP1A, anti-CYP2C, anti-CYP2D and anti-CYP2E1 antibodies did not detect any band in mouse intestinal microsomes. 5. The results suggest that mouse intestinal microsomes should be prepared with glycerol and several protease inhibitors and that Cyp3a enzymes probably play an important role in drug oxidations catalysed by mouse intestine.