Browsing by Subject "NONMEM"

Now showing 1 - 4 of 4
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    Application of pharmacometrics for covariate selection and dose optimization of tacrolimus in adult kidney transplant recipients
    (2012-12) Passey, Chaitali
    In spite of rigorous dose adjustments by way of therapeutic drug monitoring, a large proportion of kidney transplant recipients are unable to achieve the target tacrolimus trough concentrations. This is attributed to the narrow therapeutic window of the drug (10-15 ng/mL) and large inter-individual variability in pharmacokinetic parameter such as clearance. There is a need for development of clinical dosing models that can help prospectively predict the dose for an individual, especially in the critical period immediately post-transplant. Therefore, we established and quantified the effect of clinical and genetic factors on tacrolimus clearance (CL/F) using a large population of adult kidney transplant recipients. Tacrolimus troughs (n=11823) from 681 transplant recipients over the first 6-months post-transplant were analyzed using non-linear mixed effects modeling approach in NONMEM®. The troughs were characterized by a steady state infusion model. Covariates were analyzed using a forward selection (p<0.0.1) backward elimination (p<0.001) approach. We formulated an equation that predicts the CL/F of an individual based on the days post-transplant, presence of the highly influential CYP3A5*1 genotype, transplant at a steroid sparing center, age and concomitant use of a calcium channel blocker at the time of trough collection. The CL/F was seen to decrease with increasing days post transplant, transplant at a steroid sparing center and use of a calcium channel blocker. Transplant recipients with the CYP3A5*1/*3 and *1/*1 genotypes had a CL/F that was 70% and 100% higher, respectively, than those with the CYP3A5*3/*3 genotype. The dose required in order to achieve a particular target trough can be prospectively determined from this equation. The above equation was validated in a separate cohort of adult kidney transplant recipients. The equation was assessed by predictive performance in 795 transplant recipients (n=13,968 troughs) receiving tacrolimus using bias and precision. Assessment was done for the initial troughs as well as for all troughs over the entire 6 months. The equation has low bias (0.2 ng/ml) and good precision (within ± 20% for a typical trough of 10 ng/mL) in predicting initial troughs and could be safely used to predict initial doses. This is critical as an accurate initial dose will help the recipient to get to therapeutic range faster and reduce the number of out-of-range troughs. For all the troughs, over the 6 months post-transplant, the equation did better than a basic model with no covariates but had higher bias and imprecision than the prediction of initial troughs. We were presented with 119 single nucleotide polymorphisms (SNP) in this study. Due to software limitations and impracticalities associated with such a large number of covariates, we developed and validated a novel "winnowing method" of covariate selection that is able to test and select SNPs in combination. This method uses random selection, repetitions of generalized additive modeling in the R statistical package and post-hoc estimates from NONMEM®. The salient feature of this method is the creation of an index, ranging from 0-1, that defines the relative importance of the SNP when tested in a combination. With this method, we were able to select 26 SNPs out of the 119 SNPs, which included the well-established CYP3A5*1 SNP. We validated this method using a simulated dataset. In the validation dataset, the winnowing method was able to select all the important SNPs. The type I and type II error rates were 9% and 0% respectively. Although NONMEM® is the oldest and most widely used population pharmacokinetics software, several other software packages are now becoming available such as the Phoenix® NLMETM. One desirable feature in this new software package is a graphical user interface and menu-driven covariate selection options. Therefore, we compared these two software packages in terms of covariates selected and predictive performance using both clinical and simulated data. For the tacrolimus data, NONMEM® predictions had lower bias and imprecision as compared to Phoenix® NLMETM. For the clinical data, NONMEM® predictions had higher bias but were more precise than the Phoenix® NLMETM predictions.>
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    Application of Pharmacometrics to Rare Diseases
    (2016-10) Ahmed, Mariam
    Rare diseases affect an estimated 600–700 million people across the globe and are often chronic, progressive, degenerative, and life threatening.  In United States, there are more than 7,000 known rare diseases, of which less than 5% are treatable with approximately 550 approved orphan drugs. Drug development for rare disease possesses several layers of challenges. Pharmacometrics represents an attractive tool during orphan drug development as it provides a way to integrate knowledge about the disease and its treatment in a quantitative framework. These models can be utilized to optimize clinical trial designs for evaluation of treatments under development. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long-chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. We characterized the effect of LO administration on plasma C26:0 concentrations and determined whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. Non-linear mixed effects modelling was performed on 2384 samples that were collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2–3 mg/ kg with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.79). Our time-to-event analyses showed that every mg/L increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency characterized by impaired cortisol synthesis. Replacement with oral hydrocortisone (HC) does somewhat correct the resulting over-production of adrenal androgens, but significant medical problems follow these children into adulthood. To better understand dosing requirements, population pharmacokinetics of cortisol was characterized in children with CAH. Children with CAH (n=48; median [range] age and weight were: 7.1 years [1.47-18.2 years] and 29.3 kg [10.8-80.6 kg], respectively) receiving oral HC, had 12 serum samples obtained over 6 hours starting at 0800 h. Nonlinear mixed-effect modeling assuming a one-compartment model and allometric scaling was used for data analysis. The model included information on circadian rhythm from historical data to allow simulation of 24-h profiles of cortisol. Effects of disease phenotype, formulation type, pubertal stage, and sex on cortisol disposition were examined. Clearance (CL/F) and volume of distribution (V/F) were: 21.7.(WT/70)3/4 L/h and 37.6.(WT/70) L, respectively, and a resulting half-life of 0.896 hr. The bioavailability of the suspension was comparable to tablet formulation (99.6% relative to the tablet formulation). Our model-based simulations suggest many children with CAH are exposed to prolonged periods of hypocortisolemia and hyperandrogenemia over 24 hours with current hydrocortisone dosage regimens.
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    Intranasal and rectal diazepam for rescue therapy: assessment of pharmacokinetics and tolerability.
    (2010-12) Ivaturi, Vijay Deep
    The use of rectal diazepam has improved the management of acute repetitive seizures (ARS) outside a health care facility. Two placebo controlled trials have shown that rectal administration of diazepam is safe and effective for treatment of this condition. Diastat® is the only FDA approved treatment for ARS in the United States. Although some older children and adults are willing to use Diastat®, many patients in these age groups as well as physicians and caregivers object to the route of administration and instead use other therapies not approved for this purpose, receive no treatment, or use emergency medical services or acute care systems. We developed and evaluated three nasal spray formulations of diazepam which can be easily administered with rapid absorption characteristics intended as an alternative to rectal administration. One formulation used a supersaturated glycofurol based co-solvent system while the remaining two (Nas-A & Nas-B) used microemulsion based co-solvent systems. These formulations were studied for their pharmacokinetics and tolerability in healthy adult volunteers. Data from these studies were then compared to the pharmacokinetics after rectal administration using both model-based analysis (NONMEM) and graphical methods. The primary finding from this work was that, only the microemulsion-based formulations, particularly Nas-B could be used for further development as the glycofurol formulation was not well tolerated by subjects. The pharmacokinetic profiles after intranasal administration were associated with high variability. However, we are able to show that the dose-normalized partial area under the curve (AUC - an exposure parameter) after nasal administration, at times when the drug concentrations are most important, are 60-80 % of that when given via the rectal route. Given the ease and social acceptability of nasal administration compared to rectal, equivalent exposures can be easily attained by giving a second nasal dose, and we thus conclude that intranasal diazepam is a feasible and preferable alternative to rectal diazepam in the management of ARS outside a hospital. This work also provides some recommendations for future studies in the development of an intranasal product.
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    The Pharmacokinetics Of Enterohepatic Circulation
    (2015-12) Okour, Malek
    The EnteroHepatic Circulation (EHC) is defined as a process that is composed of a circuit of several steps including: liver metabolism, bile secretion, gut metabolism, and reabsorption from the gut back to the systemic circulation. The presence of EHC results in longer apparent drug half-lives and the appearance of multiple secondary peaks. Several empirical modeling strategies are present in the literature; however, they are generally deficient in their applicability to empirical modeling and/or physiological representation of the EHC process. The objective of the current analysis is to further develop our understanding of the application of modeling and simulation to drugs undergoing EHC. We propose a gallbladder-based model that provides a more physiological representation of the EHC process. The model was used in a sensitivity analysis to evaluate the effect of the extent of EHC on the pharmacokinetic profile and non-compartmental analysis (NCA) calculations. Stochastic Simulation and Estimation (SSE) analysis was conducted to compare parameter estimates from several literature EHC models following a single dose of a drug undergoing EHC. The proposed model was applied in a population pharmacokinetic analysis of unbound mycophenolic acid (MPA), total MPA, mycophenolic acid glucuronide (MPAG) and acyl-MPAG. Finally, a quantitative evaluation of the MPA exposure-response relationship was performed by building a logistic model that described the relationships between total MPA, unbound MPA and acyl-MPAG exposure variables and the probability of acute rejection and leukopenia.