Population pharmacokinetics, pharmacodynamics and pharmacogenetics modelling of oxypurinol in Hmong adults with gout and/or hyperuricemia.

AIMS: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU). METHODS: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. RESULTS: A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95% CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications. CONCLUSIONS: The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

Investigating the contribution of residual unexplained variability components on bias and imprecision of parameter estimates in population pharmacokinetic mixed-effects modeling.

In a nonlinear mixed-effects modeling (NLMEM) approach of pharmacokinetic (PK) and pharmacodynamic (PD) data, two levels of random effects are generally modeled: between-subject variability (BSV) and residual unexplained variability (RUV). The goal of this simulation-estimation study was to investigate the extent to which PK and RUV model misspecification, errors in recording dosing and sampling times, and variability in drug content uniformity contribute to the estimated magnitude of RUV and PK parameter bias. A two-compartment model with first-order absorption and linear elimination was simulated as a true model. PK parameters were clearance 5.0 L/h; central volume of distribution 35 L; inter-compartmental clearance 50 L/h; peripheral volume of distribution 50 L. All parameters were assumed to have a 30% coefficient of variation (CV). One hundred in-silico subjects were administered a labeled dose of 120 mg under 4 sample collection designs. PK and RUV model misspecifications were associated with relatively larger increases in the magnitude of RUV compared to other sources for all levels of sampling design. The contribution of dose and dosing time misspecifications have negligible effects on RUV but result in higher bias in PK parameter estimates. Inaccurate sampling time data results in biased RUV and increases with the magnitude of perturbations. Combined perturbation scenarios in the studied sources will propagate the variability and accumulate in RUV magnitude and bias in PK parameter estimates. This work provides insight into the potential contributions of many factors that comprise RUV and bias in PK parameters.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with Various CYP2C9 Genotypes under Different Cotreatments.

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high interindividual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiology-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin that integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of a single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. SIGNIFICANCE STATEMENT: The present study found that a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed-Effects Analysis.

Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed-effects modeling. Mixed linear and nonlinear elimination pathways were required to adequately describe the disposition of PM. Creatinine clearance (CrCL) was incorporated as a covariate associated with first-order elimination, representing renal clearance (ClR ) of PM. For a 70-kg patient, ClR was 14.9 L/h, Volume of distribution was 525 L, maximum rate was 81.2 mg/h, and the concentration to achieve 50% of maximum rate was 0.51 mg/L. We conducted simulations to explore the impact of CrCL as a measure of renal function and observed that when CrCL decreases from 120 to 40 mL/min, PM area under the plasma concentration-time curve (AUC) from time 0 to 8 hours and AUC increases by 9.2% and 80.9% on average after a single dose, respectively. Our data suggest that renal function has limited influence on PM exposure during the first 8 hours after dosing but has a large impact on the total exposure. Dose adjustment of cyclophosphamide may not be necessary in hematopoietic cell transplant recipients with moderate to severe kidney dysfunction to attain targeted exposures based on AUC from time 0 to 8 hours. However, dose reduction may be necessary if demonstrated at some future time that total AUC is a better surrogate for safety or toxicity.

Findings from a pilot study of buprenorphine population pharmacokinetics: A potential effect of HIV on buprenorphine bioavailability.

BACKGROUND: Buprenorphine is widely used in the treatment of opioid use disorder (OUD). There are few pharmacokinetic models of buprenorphine across diverse populations. Population pharmacokinetics (POPPK) allows for covariates to be included in pharmacokinetic studies, thereby opening the potential to evaluate the effect of comorbidities, medications, and other factors on buprenorphine pharmacokinetics. This pilot study used POPPK to explore buprenorphine pharmacokinetics in patients with and without HIV receiving buprenorphine for OUD. METHODS: Plasma buprenorphine levels were measured in 54 patients receiving buprenorphine for OUD just prior to and 2-5 h following regular buprenorphine dosing. A linear one-compartment POPPK model with first-order estimation was used to evaluate buprenorphine clearance (CL/F) and volume of distribution (V/F). Covariates included weight and HIV status. RESULTS: All HIV+ patients reported complete past-month adherence to taking antiretroviral therapy that included either efavirenz or nevirapine. Buprenorphine CL/F was 76% higher in HIV+ patients (n = 17) than HIV- patients (n = 37). Buprenorphine V/F was 41% higher in the HIV+ patients. CONCLUSIONS: POPPK can be used to model buprenorphine pharmacokinetics in a real-world clinical population. While interactions between ART and buprenorphine alter buprenorphine CL/F, we also found alteration in V/F. Proportionate changes in CL/F and V/F might indicate a primary effect on bioavailability (F) rather than two separate effects. These findings indicate reduced buprenorphine bioavailability in patients with HIV.

Comparison of Dose Adjustment Strategies for Obesity in High-dose Cyclophosphamide Among Adult Hematopoietic Cell Transplantation Recipients: Pharmacokinetic Analysis.

Cyclophosphamide (CY) is an alkylating agent widely used in the field of oncology and hematopoietic cell transplantation (HCT). It is recommended to use an adjusted body weight with an adjustment factor of 0.25 (ABW25) for dosing of CY in obese patients undergoing HCT. However, evidence based on the pharmacokinetics (PK) of CY to support this recommendation is lacking. We aimed to identify a dosing strategy of CY that achieves equivalent exposures among obese and nonobese patients. The present study is a secondary analysis of a previously conducted observational PK study of phosphoramide mustard (PM), the final cytotoxic metabolite of CY. Data were collected from 85 adults with hematologic malignancy who received a single infusion of CY 50 mg/kg, fludarabine, ± anti-thymocyte globulin, and a single fraction of total body irradiation as HCT conditioning therapy. A previously developed population PK model in these patients was used for simulations. Using individualized PK parameters from that analysis, simulations were performed to assess cumulative exposures of PM (i.e., area-under-the-curve [AUC]) resulting from 8 different dosing strategies according to various measures of body size: (1) "mg/kg" by total body weight (TBW); (2) "mg/kg" by ideal body weight (IBW); (3) "mg/kg" by fat free mass; (4) "mg/m2" by body surface area (BSA); (5) "mg/kg" by TBW combined with ABW25 (TBW-ABW25); (6) "mg/kg" by IBW combined with ABW25 (IBW-ABW25); (7) "mg/kg" by TBW combined with ABW by adjustment factor of 0.50 (TBW-ABW50); and (8) "mg" by fixed-dose. We defined equivalent exposure as the effect of obesity on PM AUC within ±20% from the PM AUC in the nonobese group, where obesity is defined based on TBW/IBW ratio (i.e., nonobese, <1.2; mildly obese, 1.2-1.5; and moderately/severely obese, >1.5). Primary and secondary outcomes were PM AUC0-8hours and PM AUC0-infinity, respectively. In the 85 patients, with the median age of 63 years (range 21-75), 46% were classified as mildly and 25% were moderately/severely obese based on the TBW/IBW ratio. Negative correlations (i.e., higher the extent of obesity, lower the PM AUC) were shown when dosing simulations were based on IBW, TBW-ABW25, and fixed dosing (P < .05). Positive correlations were shown when dosing was simulated by TBW (P < .05). None of the 8 dosing strategies attained equivalent PM AUC0-8hours between patients with versus without obesity, whereas dosing by BSA and TBW-ABW50 attained equivalent PM AUC0-infinity (P < .05). Our study predicted that the recommended ABW25 dose adjustment may result in lower exposure of CY therapy in obese patients than in nonobese. A CY dosing strategy that would result in similar PM concentrations between obese and nonobese was not identified for early exposure (i.e., PM AUC0-8hours). The data suggest though that CY dosing based on "mg/m2" by BSA or "mg/kg" by TBW-ABW50 would result in similar total exposure (i.e., PM AUC0-infinity) and may minimize exposure differences in obese and nonobese patients.

Rapid antibody responses to Epstein-Barr virus correlate with reduced severity of primary infection.

BACKGROUND: We investigated Epstein-Barr virus (EBV) antibody kinetics in university freshmen who developed laboratory-documented primary EBV infection during prospective studies and correlated these kinetics with disease severity. METHODS: EBV-naïve participants had blood collected periodically and sera tested for EBV-specific antibodies with line blot and enzyme immunoassays. The line blot assay contained EBNA-1, p18, p23, BZLF-1, p138, and p54 antigens; the enzyme immunoassay contained viral capsid antigen and EBNA-1. Severity of illness (SOI) was graded 0 (asymptomatic) to 6 (bedridden). Participants with maximum SOI scores 0-2 were compared with those whose maximum SOI scores were 3-6. Time to first antibody response was analyzed using the semi-parametric COX model. RESULTS: A total of 201 sera from 38 college students collected before, during, and after primary EBV infection were tested. Earlier antibody responses correlated with milder symptoms. This was most pronounced for late-developing antibodies. The median time to development of p18 IgG was significantly earlier among low-SOI participants (64 days) than high-SOI patients (119 days; P = 0.0003).). Participants with mild disease developed EBNA-1 antibodies sooner than participants with more severe disease (125 days versus >270 days; P = 0.017). Participants with mild disease also showed more rapid loss of antibodies against IgG EA p138 and p54 ≥12 weeks post-infection (P = 0.012 and P = 0.026, respectively). CONCLUSIONS: These data suggest that rapid antibody responses to EBV correlate with reduced severity of primary EBV infection.

Pharmacokinetic Modeling of Warfarin ІI - Model-based Analysis of Warfarin Metabolites following Warfarin Administered either Alone or Together with Fluconazole or Rifampin.

The objective of this study is to conduct a population pharmacokinetic (PK) model-based analysis on 10 warfarin metabolites (4'-, 6-, 7-, 8- and 10-hydroxylated (OH)-S- and R- warfarin), when warfarin is administered alone or together with either fluconazole or rifampin. One or two compartment PK models expanded from target mediated drug disposition (TMDD) models developed previously for warfarin enantiomers were able to sufficiently characterize the PK profiles of 10 warfarin metabolites in plasma and urine under different conditions. Model-based analysis shows CYP2C9 mediated metabolic elimination pathways are more inhibitable by fluconazole (% formation CL (CLf) of 6- and 7-OH-S-warfarin decrease: 73.2% and 74.8%) but less inducible by rifampin (% CLf of 6- and 7-OH-S-warfarin increase: 85% and 75%), compared with non-CYP2C9 mediated elimination pathways (% CLf of 10-OH-S-warfarin and CLR of S-warfarin decrease in the presence of fluconazole: 65.0% and 15.3%; % CLf of 4'- 8- and 10-OH-S-warfarin increase in the presence of rifampin: 260%, 127% and 355%), which potentially explains the CYP2C9 genotype-dependent DDIs exhibited by S-warfarin, when warfarin is administrated together with fluconazole or rifampin. Additionally, for subjects with CYP2C9 *2 and *3 variants, a model-based analysis of warfarin metabolite profiles in subjects with various CYP2C9 genotypes demonstrates CYP2C9 mediated elimination is less important and non-CYP2C9 mediated elimination is more important, compared with subjects without these variants. To our knowledge, this is so far one of the most comprehensive population-based PK analyses of warfarin metabolites in subjects with various CYP2C9 genotypes under different co-medications. Significance Statement The studies we wish to publish are potentially impactful. The need for a TMDD pharmacokinetic model and the demonstration of genotyped-dependent drug interactions may explain the extensive variability in dose-response relationships that are seen in the clinical dose adjustments of warfarin.

Pharmacokinetic Modeling of Warfarin І - Model-based Analysis of Warfarin Enantiomers with a Target Mediated Drug Disposition Model Reveals CYP2C9 Genotype-dependent Drug-drug Interactions of S-Warfarin.

The objective of this study is to characterize the impact of CYP2C9 genotype on warfarin drug-drug interactions when warfarin is taken together with fluconazole, a cytochrome P450 (CYP) inhibitor, or rifampin, a CYP inducer with a nonlinear mixed effect modeling approach. A target mediated drug disposition model with a urine compartment was necessary to characterize both S-warfarin and R-warfarin plasma and urine pharmacokinetic profiles sufficiently. Following the administration of fluconazole, our study found subjects with CYP2C9 *2 or *3 alleles experience smaller changes in S-warfarin CL compared with subjects without these alleles (69.5%, 64.8%, 59.7% and 47.8% decrease in subjects with CYP2C9 *1/*1, *1/*3, *2/*3 and *3/*3 respectively). Whereas, following the administration of rifampin, subjects with CYP2C9 *2/*3 or CYP2C9 *3/*3 experience larger changes in S-warfarin CL compared with subjects with at least one copy of CYP2C9 *1 or *1B (115%, 111%, 119%, 198% and 193% increase in subjects with CYP2C9 *1/*1, *1B/*1B, *1/*3, *2/*3 and *3/*3 respectively). The results suggest different dose adjustments are potentially required for patients with different CYP2C9 genotypes if warfarin is administered together with CYP inhibitors or inducers. Significance Statement The present study found a target mediated drug disposition model is needed to sufficiently characterize the clinical pharmacokinetic profiles of warfarin racemates under different co-treatments in subjects with various CYP2C9 genotypes, following a single dose of warfarin administration. The study also found S-warfarin, the pharmacologically more active ingredient in warfarin, exhibits CYP2C9 genotype-dependent drug-drug interactions, which indicates the dose of warfarin may need to be adjusted differently in subjects with different CYP2C9 genotypes in the presence of drug-drug interactions.

Pharmacogenetics-based population pharmacokinetic analysis for dose optimization of ritonavir-boosted atazanavir in Thai adult HIV-infected patients.

BACKGROUND: This population pharmacokinetic-pharmacogenetic study aimed to investigate the optimal dose of RTV-boosted ATV (ATV/RTV) for Thai adult HIV-infected patients. METHODS: A total of 1460 concentrations of ATV and RTV from 544 patients receiving an ATV/RTV-based regimen were analyzed. The CYP3A5 6986 A > G, ABCB1 3435 C > T, ABCB1 2677 G > T, SLCO1B1 521 T > C, and NR1I2 63396 C > T were genotyped. A population pharmacokinetic model was performed using a nonlinear mixed-effect model (NONMEM®). Monte Carlo simulations were conducted to compare the percentages of patients achieving the therapeutic range of ATV through concentrations (Ctrough). RESULTS: The apparent oral clearance of ATV (CL/FATV) without RTV was 7.69 L/h with interindividual variability (IIV) of 28.7%. Patients with CYP3A5 6986 GG had a 7.1% lower CL/FATV than those with AA or AG genotype. The CL/FATV decreased by 10.8% for females compared with males. Simulation results showed higher percentages (~70%) of patient receiving doses of 200/100 or 200/50 mg achieved the target ATV Ctrough, while more patients (~40%) receiving a standard dose (300/100 mg) had ATV Ctrough above this target. CONCLUSIONS: Both CYP3A5 6986 A > G and female decreased CL/FATV in Thai HIV-infected patients. Simulations supported that the reduced dose of ATV/RTV was sufficient to achieve the target concentration for Thai population.

Effect of HIV, antiretrovirals, and genetics on methadone pharmacokinetics: Results from the methadone antiretroviral pharmacokinetics study.

BACKGROUND: Methadone treatment of opioid use disorder in HIV-infected individuals is complicated by drug-drug interactions. Genetic and other cofactors further contribute to interindividual variability in methadone pharmacokinetics. We used population pharmacokinetics to estimate the effect of drug-drug interactions, genetics, and other cofactors on methadone pharmacokinetics in a methadone maintained population in Vietnam. METHODS: Plasma R- and S-methadone levels were measured in 309 methadone maintained individuals just before and 2-5 h following methadone dosing. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction was used to evaluate methadone clearance (CL/F) and volume of distribution (V/F). The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included HIV status, antiretroviral use (efavirenz or nevirapine), weight, BMI, age, methadone dose, and 8 single nucleotide polymorphisms in across the CYP2B6, ABCB1, and NR1I3 genes. RESULTS: Taking either efavirenz or nevirapine increased R-methadone CL/F 220%. Nevirapine and efavirenz increased S-methadone CL/F by 404% and 273%, respectively. Variants in NR1I3 increased R- and S-methadone CL/F by approximately 20% only in patients taking efavirenz. Different alleles in ABCB1 rs2032582 either increased or decreased R-methadone CL/F by 10%. The CYP 2B6*4 variant decreased S-methadone CL/F by 18%. HIV-infection increased R- and S-methadone CL/F and V/F by 24%-39%. CONCLUSIONS: The HIV antiretrovirals nevirapine and efavirenz significantly increase methadone clearance. Variants inNR1I3 increased the effect of efavirenz on methadone clearance. Other variants affecting methadone CL/F were also confirmed. To our knowledge, this is the first report of HIV itself affecting methadone pharmacokinetics.

Population Pharmacokinetic Analysis of N-Acetylcysteine in Pediatric Patients With Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant.

N-acetylcysteine (NAC) has been used in patients with cerebral adrenoleukodystrophy as an antioxidant agent in association with hematopoietic stem cell transplant (HSCT). However, an understanding of the pharmacokinetic characteristics of intravenous NAC dosing in these patients is limited. If and how NAC pharmacokinetics change following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders who underwent HSCT were included in a population pharmacokinetic analysis using nonlinear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored on 3 occasions: -7, +7, and +21 days relative to transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. The covariate OCC was modeled as a fixed-effect parameter on CL and/or V1. A 2-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for CL, central (V1), and peripheral volume (V2), and intercompartment clearance were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively, for a 70-kg person. The data only supported between-subject variability in CL (12%) and V1 (41%). Residual variability was estimated to be 16%. HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. Pharmacokinetic parameter estimates were in general comparable to those reported previously in different populations. These results suggest that dosing of NAC does not need to be altered following HSCT.

Application of Deep Neural Networks as a Prescreening Tool to Assign Individualized Absorption Models in Pharmacokinetic Analysis.

A specific model for drug absorption is necessarily assumed in pharmacokinetic (PK) analyses following extravascular dosing. Unfortunately, an inappropriate absorption model may force other model parameters to be poorly estimated. An added complexity arises in population PK analyses when different individuals appear to have different absorption patterns. The aim of this study is to demonstrate that a deep neural network (DNN) can be used to prescreen data and assign an individualized absorption model consistent with either a first-order, Erlang, or split-peak process. Ten thousand profiles were simulated for each of the three aforementioned shapes and used for training the DNN algorithm with a 30% hold-out validation set. During the training phase, a 99.7% accuracy was attained, with 99.4% accuracy during in the validation process. In testing the algorithm classification performance with external patient data, a 93.7% accuracy was reached. This algorithm was developed to prescreen individual data and assign a particular absorption model prior to a population PK analysis. We envision it being used as an efficient prescreening tool in other situations that involve a model component that appears to be variable across subjects. It has the potential to reduce the time needed to perform a manual visual assignment and eliminate inter-assessor variability and bias in assigning a sub-model.

A pharmacokinetic simulation study to assess the performance of a sparse blood sampling approach to quantify early drug exposure.

Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic (PK) information for estimating early exposure. The performance of a modeling approach was compared with a noncompartmental analysis (NCA). A simulation study was performed using literature-based models for phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA). These models were used to simulate rich concentration-time profiles from 0 to 2 h. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area under the curve (pAUC) until 2 h after the start of drug infusion. From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual population PK (PopPK) pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPEs) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ±20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81%, 92%, and 88% were significantly higher than the 72%, 80%, and 67% using the NCA approach (p < 0.05; Mann-Whitney U test). This study provides a means by which early exposure can be estimated with good precision from two concentrations and a PopPK approach. It can be applied to other settings in which early exposures are of interest.

An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.

AIMS: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH). METHODS: A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an Imax model. RESULTS: Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC50 values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 µg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC50 values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively. CONCLUSION: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 µg/mL for LEV, 11.3 to 26.7 µg/mL for PHT and 126 to 223 µg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

Manipulation of Hydrocortisone Tablets Leads to Iatrogenic Cushing Syndrome in a 6-Year-Old Girl With CAH.

Currently there are no commercially available hydrocortisone formulations for the treatment of children with congenital adrenal hyperplasia (CAH) that allow for smaller doses (0.1-1.25 mg) and incremental adjustments needed to control excess androgen production and avoid the negative effects of overtreatment. This lack of availability has led physicians to recommend dividing hydrocortisone 5-mg tablets into 4 to 6 pieces, compounding capsules or hydrocortisone suspension, or crushing 5- or 10-mg tablets in 5 or 10 mL of water. We report a case of iatrogenic Cushing syndrome in a 6-year 11-month-old girl with salt-wasting CAH treated with hydrocortisone tablets that were administered after crushing and dispersing into water to obtain the prescribed dose. She presented with poor growth, increasing body mass index (BMI), excess downy hair, round facies, and gastric ulcers. Her hydrocortisone dose was 8.1 mg/m2/day. Results for all adrenal steroid concentrations were undetectable at 8 am, 12 hours after her last dose. The year prior to presentation her parents began dissolving 10 mg of hydrocortisone in 10 mL of water and using this preparation over the course of 24 hours, which coincided with rapid increase of BMI. We switched her to a pharmacy-compounded alcohol-free hydrocortisone suspension with total daily doses ranging from 6.5 to 8.2 mg/m2/day, which resulted in resolution of her cushingoid features, a decrease in BMI, and catch-up growth. Our case highlights that manipulation of hydrocortisone tablets by parents can result in great variability in dosing and the need for commercially available pediatric formulations allowing for smaller dosing required in young children.