John T. Mondick

Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy

BackgroundDecision analysis in hospital-based settings is becoming more common place. The application of modeling and simulation approaches has likewise become more prevalent in order to support decision analytics. With respect to clinical decision making at the level of the patient, modeling and simulation approaches have been used to study and forecast treatment options, examine and rate caregiver performance and assign resources (staffing, beds, patient throughput). There us a great need to facilitate pharmacotherapeutic decision making in pediatrics given the often limited data available to guide dosing and manage patient response. We have employed nonlinear mixed effect models and Bayesian forecasting algorithms coupled with data summary and visualization tools to create drug-specific decision support systems that utilize individualized patient data from our electronic medical records systems.MethodsPharmacokinetic and pharmacodynamic nonlinear mixed-effect models of specific drugs are generated based on historical data in relevant pediatric populations or from adults when no pediatric data is available. These models are re-executed with individual patient data allowing for patient-specific guidance via a Bayesian forecasting approach. The models are called and executed in an interactive manner through our web-based dashboard environment which interfaces to the hospitals electronic medical records system.ResultsThe methotrexate dashboard utilizes a two-compartment, population-based, PK mixed-effect model to project patient response to specific dosing events. Projected plasma concentrations are viewable against protocol-specific nomograms to provide dosing guidance for potential rescue therapy with leucovorin. These data are also viewable against common biomarkers used to assess patient safety (e.g., vital signs and plasma creatinine levels). As additional data become available via therapeutic drug monitoring, the model is re-executed and projections are revised.ConclusionThe management of pediatric pharmacotherapy can be greatly enhanced via the immediate feedback provided by decision analytics which incorporate the current, best-available knowledge pertaining to dose-exposure and exposure-response relationships, especially for narrow therapeutic agents that are difficult to manage.

Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction

We performed a blinded, randomized pharmacokinetic study of milrinone in 16 neonates with hypoplastic left heart undergoing stage I reconstruction to determine the impact of cardiopulmonary bypass and modified ultrafiltration on drug disposition and to define the drug exposure during a continuous IV infusion of drug postoperatively. Neonates received an initial dose of either a 100 or 250 &mgr;g/kg of milrinone into the cardiopulmonary bypass circuit at the start of rewarming. Postoperatively, milrinone was infused to clinical needs. A mixed-effect modeling approach was used to characterize milrinone pharmacokinetics during cardiopulmonary bypass, modified ultrafiltration, and postoperatively using the NONMEM algorithm. All patients in this study demonstrated a modified ultrafiltration concentrating effect that occurred despite a modified ultrafiltration drug clearance of 3.3 mL · kg−1 · min−1. The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 &mgr;g · kg−1 · min−1 resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL · kg−1 · min−1), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL · kg−1 · min−1) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 &mgr;g · kg−1 · min−1 should be considered.

Population pharmacokinetics of ketorolac in neonates and young infants.

Although ketorolac is commonly used as an analgesic in the pediatric population, there is no information on the pharmacokinetics of ketorolac available for children less than 6 months of age. The objective of this analysis was to construct a population pharmacokinetic model to describe ketorolac disposition in young children. Three neonates and 9 infants, median (range) age 0.4-32 weeks, were administered with 0.5 mg/kg of ketorolac. The data were best described by a 2-compartment model, with an allometric expression to describe body weight effects on clearance. Estimated parameters were clearance [2.8 mL·min-1·(kg0.75)-1], intercompartmental clearance (11.5 mL/min), volume of distribution of the central compartment (535 mL), and volume of distribution of the peripheral compartment (322 mL). The clearance values in these neonates and younger group of infants are greater than that reported for older children and adults.

Population Pharmacokinetic Investigation of Actinomycin‐D in Children and Young Adults

Actinomycin‐D is an antineoplastic agent that inhibits RNA synthesis by binding to guanine residues and inhibiting DNA‐dependent RNA polymerase. Although actinomycin‐D has been used to treat rhabdomyosarcoma and Wilms tumor for more than 40 years, the dose/exposure relationship is not well characterized. The objective of this study was to develop an initial population pharmacokinetic model to describe actinomycin‐D disposition in children and young adults from which a prospective study could be designed. A total of 165 actinomycin‐D plasma concentration measurements from 33 patients, aged 1.6 to 20.3 years, were used for the analysis. The data were analyzed using nonlinear mixed‐effects modeling with the NONMEM software system. Age, weight, and gender were examined as covariates for the ability to explain interindividual variability in actinomycin‐D pharmacokinetics. The final model was qualified via predictive check and nonparametric bootstrap procedures. A 3‐compartment model with first‐order elimination was chosen as the structural model. Allometric expressions incorporating weight were used to describe the effects of body size on actinomycin‐D pharmacokinetics. Age and gender had no discernible effects on actinomycin‐D pharmacokinetics in the population studied. The predictive check showed that the developed model was able to simulate data in close agreement with the actual study observations. The availability of an initial population pharmacokinetic model to describe actinomycin‐D pharmacokinetics will facilitate the development of a large‐scale clinical trial to study the actinomycin‐D dose/exposure relationship in pediatric patients with rhabdomyosarcoma and Wilms tumor. The covariate analysis described by the current data set suggests that indices of body size captured via allometric expressions improve the partition of variation in actinomycin‐D pharmacokinetics from this pilot data set. Relationships between pharmacokinetics and toxicity will be examined in future prospective studies in which children less than 1 year old will be enrolled.

Drug Utilization in the Pediatric Intensive Care Unit: Monitoring Prescribing Trends and Establishing Prioritization of Pharmacotherapeutic Evaluation of Critically Ill Children

The primary objective of this study was to characterize the drug exposure for children hospitalized in the authors’ institutions pediatric intensive care unit for the year 2002. Secondary objectives included the examination of drug utilization differences among various age criteria and the suitability of the most prevalent resources for pediatric dosing guidance. Many of the most commonly prescribed agents in the pediatric intensive care unit fall into the broad categories of pain management/sedation and anti‐infectives. Based on the generally narrow windows afforded by each of these drug classes, it is obvious that more, well‐defined investigations in critically ill children are warranted. The existing dosing guidance for many of these agents is neither generalizable nor sufficient to accommodate the diversity in pediatric intensive care unit patients, and the current drug monographs fall short of any practical dosing information.

Model-based drug development applied to oncology

Model-based drug development (MBDD) is an approach that is used to organize the vast and complex data streams that feed the drug development pipelines of small molecule and biotechnology sponsors. Such data streams are ultimately reviewed by the global regulatory community as evidence of a drug’s potential to treat and/or harm patients. Some of this information is captured in the scientific literature and prescribing compendiums forming the basis of how new and existing agents will ultimately be administered and further evaluated in the broader patient community. As this data stream evolves, the details of data qualification, the assumptions and/or critical decisions based on these data are lost under conventional drug development paradigms. MBDD relies on the construction of quantitative relationships to connect data from discrete experiments conducted along the drug development pathway. These relationships are then used to ask questions relevant at critical development stages, hopefully, with the understanding that the various scenarios explored represent a path to optimal decision making. Oncology, as a therapeutic area, presents a unique set of challenges and perhaps a different development paradigm as opposed to other disease targets. The poor attrition of development compounds in the recent past attests to these difficulties and provides an incentive for a different approach. In addition, given the reliance on multimodal therapy, oncological disease targets are often treated with both new and older agents spanning several drug classes. As MBDD becomes more integrated into the pharmaceutical research community, a more rational explanation for decisions regarding the development of new oncology agents as well as the proposed treatment regimens that incorporate both new and existing agents can be expected. Hopefully, the end result is a more focussed clinical development programme, which ultimately provides a means to optimize individual patient care.

Delayed small bowel transit in children with cystic fibrosis and pancreatic insufficiency.

Objective: Gastrointestinal disturbances are common in people with cystic fibrosis (CF); however, motility studies in this population have yielded inconsistent results. This study examined gastric emptying (GE) and small bowel transit (SBT) time in children with CF and pancreatic insufficiency compared with a healthy adult reference group. Methods: Participants consumed an 8-ounce liquid test meal (approximately 550 calories, 32 g of fat) labeled with 300 &mgr;Ci 99m technetium (Tc) sulfur colloid. Subjects with CF received a standard dose of pancreatic enzymes before consuming the test meal. GE and SBT were measured using a standard nuclear medicine scan. GE was determined after correcting for 99mTc decay in both anterior and posterior images. SBT was determined by following the movement of the tracer from the stomach to the cecum. The percentage arrival of total small bowel activity at the terminal ileum and cecum/ascending colon at 6 hours was used as an index of SBT. A 1-way analysis of covariance was performed for comparisons between groups after adjustment for age, sex, and body mass index. Results: Subjects with CF (n = 16) had similar GE compared with the healthy reference group (n = 12); however, subjects with CF had significantly prolonged SBT time. At 6 hours, 37.2% ± 25.4% (95% CI 23.7–50.7) of the tracer reached the terminal ileum and colon compared with 68.6% ± 13.1% (95% CI 60.2–76.9) for the reference group (P < 0.001). After controlling for sex, age, and body mass index, this difference remained statistically significant (F = 12.06, adjusted R2 = 0.44, P < 0.002). Conclusions: Children with CF and pancreatic insufficiency had unaltered GE but delayed SBT time when taking pancreatic enzymes.

Diagnosing malabsorption with systemic lipid profiling: pharmacokinetics of pentadecanoic acid and triheptadecanoic acid following oral administration in healthy subjects and subjects with cystic fibrosis

Objective: A Malabsorption Blood Test (MBT) is proposed as an alternative method to the 72-hour stool and dietary collection for assessing the degree of fat malabsorption in people with pancreatic insufficiency. The MBT consists of a simultaneous oral dose of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally absorbed. The aim of this study is to demonstrate the ability of MBT to detect fat malabsorption in healthy adult subjects using the pancreatic lipase (PL) inhibitor Orlistat (Xenical®), and in subjects with CF and PI while on and off routine pancreatic enzyme doses. Materials and methods: The MBT with the PA and THA were delivered in a breakfast test meal (2.5 g PA and either 5 g or 8 g THA) to healthy adult subjects (ages 18 – 50 years, BMI 21 – 30) and to subjects with CF (> 12 years, FEV1% predicted > 40%), after a 12-hour fast and 24 hours without dairy foods. Serum levels of PA and HA were assessed by gas-liquid chromatography, from blood samples drawn prior to MBT and then hourly for 8 hours. For healthy subjects, the MBT was administered before and after Orlistat treatment, and in subjects with CF, both with subjects receiving routine pancreatic lipase treatment (“on enzyme”) and also “off enzyme” treatment. Treatment groups were compared for baseline (C0) and maximum (Cmax) plasma concentrations of PA and HA over 8 hours: area under the curve (AUC) was calculated using linear trapezoid method. The ratio of HA to PA Cmax and AUC was also calculated and compared. Results: For the healthy subjects (n = 15, 60% female, ages 21 – 49 years), absorption of HA was reduced 71% for Cmax (p < 0.001) and 65% for AUC (p = 0.001) after Orlistat treatment, and absorption of PA was unchanged. For subjects with CF (n = 6, 50% female, ages 13 – 19 years), absorption of HA was minimal with subjects “off enzymes” and increased significantly with subjects “on enzymes” while absorption of PA did not differ between groups. Enzyme administration resulted in increased Cmax HA/PA ratios from 0.02 to 0.92 and from 0.05 to 0.73 in subjects with CF receiving 5.0 g and 8.0 g of THA, respectively. AUC HA/PA ratios showed similar increases. Conclusions: In this pilot and feasibility proof-of-concept study, the MBT, utilizing the relative absorption of HA to PA, two odd-chained fatty acids, responds to changes in fat absorption in healthy subjects using a lipase inhibitor and in subjects with CF while on or off enzyme therapy. The MBT holds promise to provide a more accurate, specific and acceptable alternative to the 72-hour stool collection to quantify pancreatic-based fat malabsorption in a variety of clinical and research contexts.

Malabsorption blood test: Assessing fat absorption in patients with cystic fibrosis and pancreatic insufficiency

The malabsorption blood test (MBT), consisting of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride that requires pancreatic lipase for absorption of the heptadecanoic acid (HA), was developed to assess fat malabsorption in patients with cystic fibrosis (CF) and pancreatic insufficiency (PI). The objective was to construct a population pharmacokinetic (PK) model to describe PA and HA disposition in healthy subjects and CF subjects. A model was simultaneously fit to PA and HA concentrations, consisting of 1‐compartment disposition and a transit model to describe absorption. PA bioavailability estimates for CF subjects without pancreatic enzyme administration (1.07 [0.827, 1.42]) and with enzymes (0.88 [0.72, 1.09]) indicated PA absorption comparable to healthy subjects. HA bioavailability in CF without enzyme administration was 0.0292 (0.0192, 0.0459) and with enzymes increased to 0.606 (0.482, 0.823). In CF, compared with taking enzymes with the MBT, HA bioavailability was further decreased by factors of 0.829 (0.664, 0.979) and 0.78 (0.491, 1.13) with enzymes taken 30 and 60 minutes after MBT, respectively. The MBT detected differences in fat absorption in subjects with CF with and without enzyme administration and with changes in enzyme timing. Future studies will address application of the MBT in CF and other malabsorption diagnoses.

Plasma topiramate concentrations resulting from doses associated with neuroprotection against white matter injury and stroke in two strains of rat pups

Background:Cerebral white matter (WM) injury and stroke are common neuropathological injuries in newborns with congenital heart defects (CHDs) requiring surgery. Previous investigations in Long Evans rat pups subjected to hypoxia–ischemia found that intraperitoneal (i.p.) topiramate (TPM) at 30 mg/kg, but not 50 mg/kg, conferred neuroprotection. In Sprague-Dawley pups, a dose of 30 mg/kg protected against stroke. Concentrations associated with neuroprotective doses were not measured. The aims of this investigation were to determine concentrations associated with neuroprotective doses and to investigate the pharmacokinetics (PK) of i.p. TPM.Methods:Concentration–time data following administration of 30 and 50 mg/kg doses were analyzed using nonlinear mixed–effect modeling.Results:Mean predicted steady-state maximum and average concentrations following 30 mg/kg TPM were 31.3 and 16.8 μg/ml in Long Evans and 39.9 and 24.4 μg/ml in Sprague-Dawley pups. Mean predicted steady-state maximum and average concentrations following 50 mg/kg TPM were 52.1 and 28.1 μg/ml in Long Evans and 66.5 and 40.6 μg/ml in Sprague-Dawley pups. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.0470 ml/min and 22.2 ml, respectively, for Long Evans and 0.0325 ml/min and 19.7 ml, respectively, for Sprague-Dawley pups.Conclusion:TPM concentrations associated with neuroprotective doses were determined. Body size and strain were significant covariates on CL/F and V/F. Results provide targets for future neuroprotection studies.