Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs.

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size.

Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007.

IMPORTANCE: During pediatric drug development, dedicated pharmacokinetic studies are generally performed in all relevant age groups to support dose selection for subsequent efficacy trials. To our knowledge, no previous assessments regarding the need for an intensive pharmacokinetic study in adolescents have been performed. OBJECTIVES: To compare U.S. Food and Drug Administration (FDA)-approved adult and adolescent drug dosing and to assess the utility of allometric scaling for the prediction of drug clearance in the adolescent population. DESIGN: Adult and adolescent dosing and drug clearance data were obtained from FDA-approved drug labels and publicly available databases containing reviews of pediatric trials submitted to the FDA. Dosing information was compared for products with concordant indications for adolescent and adult patients. Adolescent drug clearance was predicted from adult pharmacokinetic data by using allometric scaling and compared with observed values. MAIN OUTCOMES AND MEASURES: Adolescent and adult dosing information and drug clearance. RESULTS: There were 126 unique products with pediatric studies submitted to the FDA since the FDA Amendments Act of 2007, of which 92 had at least 1 adolescent indication concordant with an adult indication. Of these 92 products, 87 (94.5%) have equivalent dosing for adults and adolescent patients. For 18 of these 92 products, a minimum weight or body surface area threshold is recommended for adolescents to receive adult dosing. Allometric scaling predicted adolescent drug clearance with an overall mean absolute percentage error of 17.0%. CONCLUSIONS AND RELEVANCE: Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA.

Efficacy of pulmonary insulin delivery in diabetic rats: use of a model-based approach in the evaluation of insulin powder formulations.

The potential of N-trimethyl chitosan (TMC) with two degrees of quaternization (DQ), TMC20 (DQ 20%, as a mucoadhesive) and TMC60 (DQ 60%, as a mucoadhesive and a permeation enhancer), and dextran (as a non-mucoadhesive and non-permeation enhancer) microparticles as carriers for pulmonary delivery of insulin was studied in diabetic rats. The impact of the powder formulation on insulin bioavailability and its pharmacological effect was evaluated using a population pharmacokinetic-pharmacodynamic (PKPD) model. Insulin-loaded microparticles were prepared by a supercritical fluid (SCF) drying technique. They had a median volume diameter and median volume aerodynamic diameter of about 6-10 microm and 4 microm, respectively. The PK of insulin in the diabetic rats was analyzed by a one-compartment disposition model and the PD was described by the minimal model of glucose disappearance. The bioavailability of the pulmonarily administered dextran-, TMC20- and TMC60-insulin microparticles relative to subcutaneously (SC) administered insulin, was 0.48, 0.59 and 0.95, respectively. Histological examinations of the rats' lungs did not show any local adverse reactions after single administration of insulin powders. The pharmacodynamic model could describe the insulin-glucose relationship and pharmacodynamic efficiency of insulin formulations, which was about 0.6(*)10(-5) ml/microU, irrespective of the formulations. The current findings suggest that TMC microparticles are a promising vehicle for pulmonary delivery of insulin.

Use of oral glucose minimal model-derived index of insulin sensitivity in subjects with early type 1 diabetes mellitus.

Insulin resistance plays an important role during various stages of the type 1 diabetes mellitus disease process. Unfortunately, many of the techniques used to measure insulin sensitivity are experimentally laborious and time-consuming and are thus impractical for larger clinical and population studies. Therefore, in this study, we obtain estimates of insulin sensitivity from a simpler experiment, the oral glucose tolerance test (OGTT), and compare them with those from a frequently sampled intravenous glucose tolerance test (FSIGT) in a population of subjects defined as having early type 1 diabetes mellitus (abnormal 2-hour glucose on OGTT) and a group of healthy controls. A total of 19 subjects were studied. Eight antibody-positive first- or second-degree relatives of patients with type 1 diabetes mellitus and 11 healthy controls underwent both a 3-hour OGTT and an insulin-modified FSIGT on separate days. Indices of insulin sensitivity (SI) were estimated from the recently derived oral glucose minimal model and the original minimal model of glucose kinetics for the OGTT and FSIGT, respectively. Estimates of SI from the OGTT correlated closely with those from the FSIGT in both early type 1 diabetes mellitus (rs=0.76, P = .04) and healthy control (rs = 0.67, P = .03) populations. This preliminary study demonstrates the usefulness of OGTT-derived estimates of insulin sensitivity in an early type 1 diabetes mellitus population. Given the simplicity of the OGTT relative to the traditional methods of measuring SI, the oral glucose minimal model may be appropriate for large population studies and clinical trials.

Population approaches to estimate minimal model indexes of insulin sensitivity and glucose effectiveness using full and reduced sampling schedules.

The intravenous glucose tolerance test (IVGTT) interpreted with the minimal model provides individual indexes of insulin sensitivity (S(I)) and glucose effectiveness (S(G)). In population studies, the traditional approach, the standard two-stage (STS) method, fails to account for uncertainty in individual estimates, resulting in an overestimation of between-subject variability. Furthermore, in the presence of reduced sampling and/or insulin resistance, individual estimates may be unobtainable, biasing population information. Therefore, we investigated the use of two population approaches, the iterative two-stage (ITS) method and nonlinear mixed-effects modeling (NM), in a population (n = 235) of insulin-sensitive and insulin-resistant subjects under full (FSS, 33 samples) and reduced [RSS(240-min), 13 samples and RSS(180-min), 12 samples] IVGTT sampling schedules. All three population methods gave similar results with the FSS. Using RSS(240), the three methods gave similar results for S(I), but S(G) population means were overestimated. With RSS(180), S(I) and S(G) population means were higher for all three methods compared with their FSS counterparts. NM estimated similar between-subject variability (19% S(G), 53% S(I)) with RSS(180), whereas ITS showed regression to the mean for S(G) (0.01% S(G), 56% S(I)) and STS provided larger population variability in S(I) (29% S(G), 91% S(I)). NM provided individual estimates for all subjects, whereas the two-stage methods failed in 16-18% of the subjects using RSS(180) and 6-14% using RSS(240). We conclude that population approaches, specifically NM, are useful in studies with a sparsely sampled IVGTT ( approximately 12 samples) of short duration ( approximately 3 h) and when individual parameter estimates in all subjects are desired.

Integrated model of hepatic and peripheral glucose regulation for estimation of endogenous glucose production during the hot IVGTT.

We have developed a new model to describe endogenous glucose kinetics during a labeled (hot) intravenous glucose tolerance test (IVGTT) to derive a time profile of endogenous glucose production (EGP). We reanalyzed data from a previously published study (P. Vicini, J. J. Zachwieja, K. E. Yarasheski, D. M. Bier, A. Caumo, and C. Cobelli. Am J Physiol Endocrinol Metab 276: E285-E294, 1999), in which insulin-modified [6,6-2H2]glucose-labeled IVGTTs (0.33 g/kg glucose) were performed in 10 normal subjects. In addition, a second tracer ([U-13C]glucose) was infused in a variable rate to clamp the endogenous glucose tracer-to-tracee ratio (TTR). Our new model describing endogenous glucose kinetics was incorporated into the two-compartment hot minimal-model structure. The model gave estimates of glucose effectiveness [1.54 +/- 0.31 (SE) ml x kg(-1) x min(-1)], insulin sensitivity (37.74 +/- 5.23 10(4) dl x kg(-1) x min(-1) x microU(-1) x ml), and a new parameter describing the sensitivity of EGP to the inhibitory effect of insulin (IC50 = 0.0195 +/- 0.0046 min(-1)). The model additionally provided an estimate of the time course of EGP showing almost immediate inhibition, followed by a secondary inhibitory effect caused by infusion of insulin, and a large overshoot as EGP returns to its basal value. Our estimates show very good agreement with those obtained via deconvolution and the model-independent TTR clamp technique. These results suggest that the new integrated model can serve as a simple one-step approach to obtain metabolic indexes while also providing a parametric description of EGP.