Translational Population-Pharmacodynamic Modeling of a Novel Long-Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia.

Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to characterize inclisiran's dose-related LDL-C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate the long duration of action, the K-PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL-C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C baseline levels as important factors for the effects of LDL-C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL-C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months.

Population pharmacokinetics and exposure-response of trilaciclib in extensive-stage small cell lung cancer and triple-negative breast cancer.

AIMS: Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4/6 inhibitor that provides multilineage protection from chemotherapy-induced myelosuppression. This analysis aimed to characterize the population pharmacokinetics (PK) of trilaciclib, identify potential covariates influencing trilaciclib PK, and evaluate exposure-response relationships in extensive-stage small cell lung cancer (ES-SCLC) and triple-negative breast cancer (TNBC) trials. METHODS: Population PK analysis was performed using data from healthy volunteers (n = 72), patients with ES-SCLC (n = 111) and patients with TNBC (n = 14). Exposure-response analyses were conducted to investigate the impact of trilaciclib exposure (AUC) on myeloprotective efficacy, antitumour efficacy and safety. Logistic regression and Cox regression models were used for binary and time-to-event endpoints, respectively. RESULTS: Trilaciclib PK was described by a three-compartment model. Sex, body surface area, baseline albumin concentration and age were identified as significant covariates on trilaciclib PK but did not have clinically relevant impact on exposure. Based on exposure-response analyses, lower and higher exposures of trilaciclib at clinical doses (200-280 mg/m2 ) were associated with similar myeloprotective effects. Trilaciclib exposure did not impact the antitumour effects of chemotherapy. Higher exposure to trilaciclib was associated with higher probabilities of headache, phlebitis/thrombophlebitis and injection site reactions. CONCLUSION: No dose adjustments are required based on the covariates tested. Trilaciclib resulted in optimal myeloprotective effects with no impact on antitumour effects of chemotherapy. However, higher exposure increased the probabilities of adverse events. The data further support selection of the recommended phase 2 dose (trilaciclib 240 mg/m2 ).

An Evaluation Approach for the Performance of Dosing Regimens in Attention-Deficit/Hyperactivity Disorder Treatment.

OBJECTIVE: Stimulant medications, with methylphenidate as the main agent, are the most prescribed for the treatment of attention-deficit/hyperactivity disorder. Nevertheless, real challenges still remain for clinicians concerned with adaptation of the therapeutic regimens, in terms of doses and timing, to children's daily activities. The aim of this study was to optimize short-acting methylphenidate regimens according to specific children's needs by evaluating the performance of a particular regimen through a web-based application. METHODS: In this article, accounting for day-to-day children's activities and using up-to-date pharmacokinetic knowledge of methylphenidate, we propose a computational approach for the identification of the most suitable dosing regimens of immediate-release formulations of methylphenidate based on constraints on drug concentration and time frame of activities, defined through therapeutic boxes. To assess the performance of these regimens, time- and concentration-based therapeutic indicators, as well as a roller coaster effect, are proposed. RESULTS: A web-based interface that can serve as an educational tool for clinicians and patients has been developed based on the proposed approach for the evaluation of dosing regimens. Comparison of those optimal regimens identified by our method with the well-accepted regimens defined in the NIMH Collaborative Multisite Multimodal Treatment study of Children with attention-deficit/hyperactivity disorder indicates that there is still room for improvement in the current practice especially for the last dose administration to avoid side effects such as sleep disturbance. CONCLUSION: The developed approach and its associated web-based interface provide an efficient way to evaluate and adapt the methylphenidate regimens to children's daily activities. In addition, this approach could be used as proof of concept to further implement combination of short- and long-acting methylphenidate.

Comparison of blood microsampling with DBS and conventional blood collection techniques used in a midazolam biostudy.

BACKGROUND: Quantitative DBS LC-MS/MS assay for midazolam was used to compare two sample collection techniques (venipuncture and finger prick) and the midazolam concentrations measured in plasma samples, DBS and dried plasma spots. METHODOLOGY: Midazolam was extracted from DBS cards and compared with whole blood collected from usual venipuncture. Dried plasma spots were also compared with plasma. The blood volume used as well as the temperature impact during the blood and plasma deposits was evaluated. Midazolam was administrated to six healthy subjects during a clinical trial to obtained blood and plasma samples for the statistical comparison. CONCLUSION: The method for midazolam using DBS was validated and showed an excellent performance. Excellent correlations were observed when the same collection procedures were used.

Modeling Testosterone Circadian Rhythm in Hypogonadal Males: Effect of Age and Circannual Variations.

The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysis. The circadian rhythm of the testosterone was described by a stretched cosine function. Model parameters were estimated using NONMEM(®) 7.3. The effect of different covariates on the testosterone levels was investigated. Model evaluation was performed using non-parametric bootstrap and predictive checks. A stretched cosine function deeply improved the data goodness of fit compared to the standard trigonometric function (p < 0.001; ΔOFV = -204). The effect of the age and the semester, defined as winter and spring versus summer and fall, were significantly associated with the baseline levels of testosterone (p < 0.001, ΔOFV = -15.6, and p < 0.001, ΔOFV = -47.0). Model evaluation procedures such as diagnostic plots, visual predictive check, and non-parametric bootstrap evidenced that the proposed stretched cosine function was able to model the time course of the diurnal testosterone levels in hypogonadal males with accuracy and precision. The circadian rhythm of the testosterone levels was better predicted by the proposed stretched cosine function than a standard cosine function. Testosterone levels decreased by 5.74 ng/dL (2.4%) every 10 years and were 19.3 ng/dL (8.1%) higher during winter and spring compared to summer and fall.

Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects.

The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.

Limited sampling strategies for estimating intravenous and oral cyclosporine area under the curve in pediatric hematopoietic stem cell transplantation.

BACKGROUND: The optimal monitoring strategy for cyclosporine (CsA) in pediatric hematopoietic stem cell transplantation (HSCT) patients remains unclear. Although there is a growing interest in the use of the area under the concentration-time curve (AUC), measurement of AUC in clinical settings is often impractical. The objective of this study was to identify and validate limited sampling strategies (LSSs) for the prediction of CsA AUC after intravenous (IV) and oral (PO) administration in this population. METHODS: Sixty-eight pediatric patients who underwent HSCT and received CsA were investigated. Twelve-hour pharmacokinetic profiles (n = 138) performed per standard of care were collected. Weighted multiple linear regression was used to investigate all possible LSSs consisting of 4 or less concentration-time points. Their predictive performance was evaluated by leave one out cross validation and external validation by measuring the root mean squared relative error (RMSE%) and the 95th percentile of the absolute relative error (AE%). Values less than 20% were considered clinically acceptable. RESULTS: Nine LSSs (4 IV and 5 PO) convenient for clinical application proved to have clinically acceptable performance. Notably, LSS based on C0, C2, and C4 was found to be accurate for estimation of CsA exposure after both IV and PO administration with the 95th percentile of AE% of 19.7% and 17.5%, respectively. CONCLUSIONS: LSSs using 3 or 4 concentration-time points obtained within 4 hours postdose provide a convenient and reliable method to estimate CsA exposure in this population. These LSSs may facilitate future research aiming at better defining the relationship between AUC and clinical outcomes.

Population pharmacokinetic analysis of tesamorelin in HIV-infected patients and healthy subjects.

BACKGROUND AND OBJECTIVES: Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequently, the aim of this study was to characterize the population pharmacokinetics of tesamorelin in HIV-infected patients and healthy subjects. METHODS: A total of 38 HIV-infected patients and healthy subjects receiving subcutaneous tesamorelin doses of 1 or 2 mg administered daily during 14 consecutive days were included in the analysis. An open one-compartment model with first- and zero-order absorption and first-order elimination was developed to best describe the data using NONMEM(®) VII. The effect of different covariates on tesamorelin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. RESULTS: Plasma clearance and its interindividual variability [% coefficient of variation (CV)] was estimated to be 1,060 L/h (33.6 %). Volume of distribution was calculated to be 200 L (17.7 %). Age, body size measures, race and health status were not related to tesamorelin pharmacokinetic parameters within the range of covariates studied. The fraction of tesamorelin absorbed by a first-order process is 13.1 % higher on day 14 compared with day 1. Predictive checks and non-parametric bootstrap demonstrated that the model is appropriate in describing the time course of tesamorelin plasma concentrations in both HIV-infected patients and healthy subjects. CONCLUSIONS: An open one-compartment model with first and zero order absorption processes and linear elimination is suitable to characterize the pharmacokinetics of tesamorelin. The fraction of tesamorelin absorbed by a first-order process evolves with time. No clinically relevant covariates were identified as predictors of tesamorelin pharmacokinetics.

Bayesian approach for the estimation of cyclosporine area under the curve using limited sampling strategies in pediatric hematopoietic stem cell transplantation.

BACKGROUND: The optimal marker for cyclosporine (CsA) monitoring in transplantation patients remains controversial. However, there is a growing interest in the use of the area under the concentration-time curve (AUC), particularly for cyclosporine dose adjustment in pediatric hematopoietic stem cell transplantation. In this paper, we develop Bayesian limited sampling strategies (B-LSS) for cyclosporine AUC estimation using population pharmacokinetic (Pop-PK) models and investigate related issues, with the aim to improve B-LSS prediction performance. METHODS: Twenty five pediatric hematopoietic stem cell transplantation patients receiving intravenous and oral cyclosporine were investigated. Pop-PK analyses were carried out and the predictive performance of B-LSS was evaluated using the final Pop-PK model and several related ones. The performance of B-LSS when targeting different versions of AUC was also discussed. RESULTS: A two-compartment structure model with a lag time and a combined additive and proportional error is retained. The final covariate model does not improve the B-LSS prediction performance. The best performing models for intravenous and oral cyclosporine are the structure ones with combined and additive error, respectively. Twelve B-LSS, consisting of 4 or less sampling points obtained within 4 hours post-dose, predict AUC with 95th percentile of the absolute values of relative prediction errors of 20% or less. Moreover, B-LSS perform better for the prediction of the 'underlying' AUC derived from the Pop-PK model estimated concentrations that exclude the residual errors, in comparison to their prediction of the observed AUC directly calculated using measured concentrations. CONCLUSIONS: B-LSS can adequately estimate cyclosporine AUC. However, B-LSS performance is not perfectly in line with the standard Pop-PK model selection criteria; hence the final model might not be ideal for AUC prediction purpose. Therefore, for B-LSS application, Pop-PK model diagnostic criteria should additionally account for AUC prediction errors.

Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations.

The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and <30 mL/min). Cmax was not statistically different between the groups, while AUC and T1/2el increased, and CL/F decreased, with increasing severity of CKD. Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.

Compliance spectrum as a drug fingerprint of drug intake and drug disposition.

Since drug related variability arises from different origins, particularly driven by the behaviour or physiology of the patient, the problems of drug intake and drug disposition are separately presented in general. To overcome the potential drawbacks of this artificial split, we propose in this paper a combined illustrative approach, named compliance spectrum, such that these two subprocesses can be equitably studied and visualized. We construct the compliance spectrum based on the Bayesian decision method we previously developed for the inverse problem of patient compliance within the framework of Population-PK. This spectrum provides an intuitive and interactive way to evaluate the relationship between drug intake and drug disposition along with their consequences on PK profile. As well, it opens a new direction for model quality diagnostic.

A Bayesian approach for the estimation of patient compliance based on the last sampling information.

Poor adherence to a drug prescription significantly impacts on the efficacy and safety of a planned therapy. The relationship between drug intake and pharmacokinetics (PK) is only partially known. In this work, we focus on the so-called "inverse problem", concerned with the issue of retracing the patient compliance scenario using limited clinical knowledge. Using a reported Pop-PK model of imatinib, and accounting for the variability around its PK parameters, we were able to simulate a whole range of drug concentration values at a specific sampling point for a population of patients with all possible drug compliance profiles. Using a Bayesian decision rule, we developed a methodology for the determination of the associated compliance profile prior to a given sampling value. The adopted approach allows, for the first time, to quantitatively acquire knowledge about the compliance patterns having a causal effect on a given PK. Moreover, using a simulation approach, we were able to evaluate the evolution of success rate of the retracing process in terms of the considered time period before sampling as well as the model-inherited variability. In conclusion, this work allows, from a probability viewpoint, to propose a solution for this inverse problem of compliance determination.