Connecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model.

The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease.

BACKGROUND: Vedolizumab, an anti-α(4)ß(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. AIMS: To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling. METHODS: Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. RESULTS: Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L). CONCLUSIONS: Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

BACKGROUND: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. METHODS: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. RESULTS: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. CONCLUSIONS: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. CLINICAL TRIAL REGISTRATION: NCT01408823.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

Population pharmacokinetic modeling of pantoprazole in pediatric patients from birth to 16 years.

The population pharmacokinetics of pantoprazole was characterized in pediatric patients from birth to 16 years using NONMEM and evaluated via bootstrap and predictive check. Data were described using a 2-compartment model with a typical parameterized in terms of clearance (CL) (95% CI) of 1.93 L per hour (1.53, 2.61), given the reference covariates (female, full term, extensive/unknown CYP2C19 metabolizer status, non-African American, 10 kg weight, intravenous or tablet administration). Pantoprazole pharmacokinetic parameters appear to be similar in pediatric patients compared to adults when allometrically scaled. The effect of age on allometrically scaled CL was best described by a sigmoid Emax model with the age effect reaching an asymptote approximately equal to the adult CL by 1 year. CYP2C19 poor metabolizers exhibited reduced CL with the point estimate and 95% CI more than 70% lower than the typical value. Simulations from the final model indicated that the 1.2-mg/kg dose provides the best comparison to adults.

Quantitative assessment of exposure-response relationships for the efficacy and tolerability of varenicline for smoking cessation.

Population exposure-response analyses involving approximately 2,000 cigarette smokers provided an integrated understanding of dose, exposure, patient characteristics, and response relating to the efficacy and tolerability of varenicline for smoking cessation. Full models with a linear function of area under the concentration-time curve at steady state AUC(0-24)(ss) and covariate effects on the baseline probability of response were constructed. Logistic regression results consistently showed that the end-of-treatment abstinence rate increased with increasing varenicline exposure, from 38% at 0.5 mg b.i.d. to 56% at 1 mg b.i.d. (vs. 22% for placebo). Baseline smoking status and age were predictive of smoking cessation, whereas race and gender showed little or no influence. Nausea was the most common adverse event, with an incidence that was gender-related and that increased with varenicline exposure; at a dosage of 1 mg b.i.d. the predicted probability of nausea relative to placebo was 24 vs. 7% in male subjects and 40 vs. 14% in female subjects. The incidence of nausea also showed a decreasing trend with time.

Exposure-response modeling and clinical trial simulation of the effect of tolterodine on QT intervals in healthy volunteers.

The objective of this analysis was to explore exposure-response modeling of data from a thorough QT (TQT) study of tolterodine in CYP2D6 extensive (EMs) and poor metabolizers (PMs). Crossover treatments of the TQT study included the recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo. The concentration-response relationships for the QTc effects of moxifloxacin and tolterodine were described using a linear model with baseline effect, placebo effect, and a drug effect. The mixed effects modeling approach, using the first order conditional estimation method, was implemented in NONMEM. Simulated data from 250 trial replicates were used for limited predictive check and to describe the expected extreme responders in this study, under the derived model and point estimates. Modeling results for tolterodine showed linear concentrationdependent increases in QTc interval, with no difference in slopes between EMs and PMs. Modelpredicted QTc prolongations for tolterodine and moxifloxacin were consistent with their respective observed mean results. No subjects were predicted to have increases of > 60 milliseconds (ms); the predicted incidence of borderline QTc increases (> 30 and ≤ 60 ms) remained low at the supratherapeutic tolterodine dose in both PMs (9.1%) and EMs (3.9%). In conclusions, this analysis supports our clinical experience that tolterodine does not have a clinically significant effect on QT interval.

Population pharmacokinetics of fluconazole in young infants.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Mathematics for understanding disease.

The application of mathematical models to reflect the organization and activity of biological systems can be viewed as a continuum of purpose. The far left of the continuum is solely the prediction of biological parameter values, wherein an understanding of the underlying biological processes is irrelevant to the purpose. At the far right of the continuum are mathematical models, the purposes of which are a precise understanding of those biological processes. No models in present use fall at either end of the continuum. Without question, however, the emphasis in regards to purpose has been on prediction, e.g., clinical trial simulation and empirical disease progression modeling. Clearly the model that ultimately incorporates a universal understanding of biological organization will also precisely predict biological events, giving the continuum the logical form of a tautology. Currently that goal lies at an immeasurable distance. Nonetheless, the motive here is to urge movement in the direction of that goal. The distance traveled toward understanding naturally depends upon the nature of the scientific question posed with respect to comprehending and/or predicting a particular disease process. A move toward mathematical models implies a move away from static empirical modeling and toward models that focus on systems biology, wherein modeling entails the systematic study of the complex pattern of organization inherent in biological systems.

Population pharmacokinetics and pharmacodynamics of sotalol in pediatric patients with supraventricular or ventricular tachyarrhythmia.

AIMS: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT). METHODS: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m2 sotalol, extensive blood samples (n = 10) were taken. The PK-PD study used a dose escalation design with doses of 10, 30, and 70 mg/m2, each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology. RESULTS: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E0 were 86.7 and 14.4%, respectively. CONCLUSIONS: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc-C relation, while the RR-C relation shows age or BSA dependency.

The use of multiple doses and pharmacodynamic system analysis to distinguish between dispositional delays and time-variant pharmacodynamics.

Pharmacokinetic-pharmacodynamic modeling algorithms, in general, rely on hysteresis minimization techniques that assume time-invariant pharmacodynamics (constant biophase concentration-effect relationships). When time-variant pharmacodynamics are observed, a specific model for tolerance or sensitization is required. However, with single dosing, hysteresis that results from a time-variant biophase concentration-effect relationship cannot be distinguished from hysteresis caused by dispositional delays. This can lead to the inappropriate minimization of hysteresis. As an approach to this problem, simulated and real kinetic-dynamic data were analyzed with the pharmacodynamic system analysis program ATTRACT. The use of a multiple dosing regimen and this hysteresis minimization algorithm resulted in a simple diagnostic test to distinguish between dispositional effects of acute tolerance and sensitization.

Distinction between the in vitro and in vivo inhibitory effects of morphine on lymphocyte proliferation based on agonist sensitivity and naltrexone reversibility.

We have previously reported that administration of a single dose of morphine (25 mg/kg) to rats results in a naltrexone-sensitive suppression of mitogen-stimulated lymphocyte proliferation. To further delineate the site of action of this inhibitory effect, the in vitro and in vivo effects of morphine on mitogen-stimulated lymphocyte proliferation were examined. In vitro, concentrations of morphine exceeding 0.1 mM exhibited a dose-dependent inhibition of Concanavalin A-induced proliferation of both whole blood and splenic lymphocytes. This inhibitory effect of morphine on lymphocyte proliferation was not attenuated by co-incubation with the opioid antagonist naltrexone (0.25 mM). These data indicate that the in vitro inhibitory effects of morphine occur at only high concentrations and are not opioid receptor mediated. In vivo, a dose-dependent inhibition of blood lymphocyte proliferation was also observed 2 h following the subcutaneous injection of morphine. In contrast to these effects, proliferation of splenic lymphocyte cultures was not significantly inhibited by morphine at doses of up to 40 mg/kg. However, following morphine administration, a greater than 90% inhibition of proliferation was obtained in cultures containing either whole blood or Ficoll-separated lymphocytes, indicating that plasma was not a contributory factor in the differential sensitivity of blood and splenic lymphocyte responses to morphine. Moreover, in these experiments, significant inhibition of lymphocyte proliferation occurred at plasma concentrations that were two orders of magnitude less than those required to produce inhibition in vitro. The in vivo inhibition of lymphocyte proliferation by morphine (10 mg/kg) was completely antagonized by pretreatment with naltrexone (5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)