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A distributed delay approach was proposed in this paper to model delayed outcomes in pharmacokinetics and pharmacodynamics studies. This approach was shown to be general enough to incorporate a wide array of pharmacokinetic and pharmacodynamic models as special cases including transit compartment models, effect compartment models, typical absorption models (either zero-order or first-order absorption), and a number of atypical (or irregular) absorption models (e.g., parallel first-order, mixed first-order and zero-order, inverse Gaussian, and Weibull absorption models). Real-life examples were given to demonstrate how to implement distributed delays in Phoenix® NLME™ 8.0, and to numerically show the advantages of the distributed delay approach over the traditional methods.

Breakthrough bleeding (BTB) is a common side effect of hormonal contraception and is thought to impact adherence to combined oral contraceptives (COCs) but respective dose–response relationships are not yet fully understood. Therefore, the objective of this model‐based meta‐analysis (MBMA) was to establish dose–response for COCs containing different progestin/EE combinations using BTB as the pharmacodynamic endpoint. Data from 25 studies containing BTB information of 4 progestins (desogestrel, drospirenone, gestodene, and levonorgestrel) in combination with ethinyl estradiol (EE) at various dose levels was used for this analysis. The results of our MBMA show that BTB is significantly increased upon initiation of COC use but subsides over time. The time needed for BTB to return to baseline depends on the EE dose and differs marginally between progestins during the initial months of use at the same EE dose. BTB typically returns to baseline within 3 months at the highest (30 μg) dose, whereas it can take significantly longer to reestablish a regular bleeding pattern at lower EE doses (15 and 20 μg), irrespective of the progestin used. The dose–response relationships established for BTB across different progestin/EE combinations can now be used to support the selection of optimal COC dosing/treatment regimens and serve as the scientific basis for evaluating the impact of clinically relevant factors, including drug–drug interactions and demographics, on BTB.

Neuropathic pain, often associated with diabetic neuropathy or nerve compression injuries, arises from damage or dysfunction in the somatosensory nervous system. Tramadol, frequently prescribed for this pain, has its fraction unbound and that of its active metabolite (M1) significantly altered by diabetes. Yet, dosing adjustments for diabetic neuropathic pain remain underexplored. This study developed a comprehensive population pharmacokinetics/pharmacodynamics (PK/PD) model for tramadol and its major metabolites, focusing on diabetes's impact on PK and PK‐PD relationship to identify optimal dosing regimens. Data from patients with chronic neuropathic pain on oral tramadol were used to develop enantiomer‐specific population models, considering both total and unbound concentrations. Tramadol's PK was best described by a two‐compartment model with Weibull absorption and linear elimination and a one‐compartment model with enterohepatic circulation and first‐pass metabolism for the active M1. Simulations showed higher unbound fractions of the active M1 in patients with type 1 and type 2 diabetes. Despite a 67% and 14% reduction in the AUC of total (1R,2R)‐M1 in patients with type 1 and type 2 diabetes, respectively, the AUC of unbound (1R,2R)‐M1 remained consistent. The unbound concentration of the active M1 required to achieve 50% of the maximum pain reduction (IC50) was lower in patients with diabetes, indicating increased sensitivity to the drug. This model‐based approach provides valuable dosing guidance, suggesting once‐daily dosing treatments in patients with diabetes and twice‐daily dosing for patients with neuropathic pain secondary to nerve compression mechanisms.

Racemic praziquantel (PZQ) is the standard treatment for schistosomiasis and liver fluke infections (opisthorchiasis and clonorchiasis). The development of an optimal pediatric formulation and dose selection would benefit from a population pharmacokinetic (popPK) model. A popPK model was developed for R-PZQ, the active enantiomer of PZQ, in 664 subjects, 493 African children (2–15 years) infected with Schistosoma mansoni and S. haematobium, and 171 Lao adults (15–78 years) infected with Opisthorchis viverrini. Racemate tablets were administered as single doses of 20, 40 and 60 mg/kg in children and 30, 40 and 50 mg/kg in 129 adults, and as 3 × 25 mg/kg apart in 42 adults. Samples collected by the dried-blood-spot technique were assayed by LC-MS/MS. A two-compartment disposition model, with allometric scaling and dual first-order and transit absorption, was developed using Phoenix™ software. Inversely parallel functions of age described the apparent oral bioavailability (BA) and clearance maturation in children and ageing in adults. BA decreased slightly in children with dose increase, and by 35% in adults with multiple dosing. Crushing tablets for preschool-aged children increased the first-order absorption rate by 64%. The mean transit absorption time was 70% higher in children. A popPK model for R-PZQ integrated African children over 2 years of age with schistosomiasis and Lao adults with opisthorchiasis, and should be useful to support dose optimization in children. In vitro hepatic and intestinal metabolism data would help refining and validating the model in younger children as well as in target ethnic pediatric and adult groups.

The multidrug resistance protein 1 (MDR1; P-glycoprotein) has been associated with efflux of chemotherapeutic agents from tumor cells and with poor patient prognosis. This study evaluated the feasibility of non-invasive, non-radioactive near infrared (NIR) imaging methodology for detection of MDR1 functional activity in tumors. Initial accumulation assays were conducted in MDR1-overexpressing MDCK cells (MDCK-MDR1) and control MDCK cells (MDCK-CT) using the NIR dyes indocyanine green (ICG), IR-783, IR-775, rhodamine 800, XenoLight DiR, and Genhance 750, at 0.4 μM-100 μM. ICG and IR-783 were also evaluated in HT-29 cells in which MDR1 overexpression was induced by colchicine (HT-29-MDR1) and their controls (HT-29-CT). optical imaging studies were conducted using immunodeficient mice bearing HT-29-CT and HT-29-MDR1 xenografts. ICG's emission intensity was 2.0- and 2.2-fold higher in control versus MDR1-overexpressing cells, in MDCK and HT-29 cell lines, respectively. The respective IR-783 control:MDR1 ratio was 1.4 in both MDCK and HT-29 cells. Optical imaging of mice bearing HT-29-CT and HT-29-MDR1 xenografts revealed a statistically non-significant, 1.7-fold difference ( > 0.05) in ICG emission intensity between control and MDR1 tumors. No such differences were observed with IR-783. ICG and IR-783 appear to be weak MDR1 substrates. , low sensitivity and high between-subject variability impair the ability to use the currently studied probes as markers of tumor MDR1 activity. The results suggest that, for future use of this technology, additional NIR probes should be screened as MDR1 substrates.

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD[sub.3] ) and its three major metabolites, 25-hydroxyvitamin D[sub.3] (25D[sub.3] ), 1,25-dihydroxyvitamin D[sub.3] (1,25D[sub.3] ), and 24,25-dihydroxyvitamin D[sub.3] (24,25D[sub.3] ), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD[sub.3] (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD[sub.3] and its metabolites. The simultaneous fit of a two-compartment model for VitD[sub.3] and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD[sub.3] and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD[sub.3] and metabolites. This is the first reported population pharmacokinetic modeling of VitD[sub.3] and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D[sub.3] concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD.

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD3) and its three major metabolites, 25-hydroxyvitamin D3 (25D3), 1,25-dihydroxyvitamin D3 (1,25D3), and 24,25-dihydroxyvitamin D3 (24,25D3), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD3 (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD3 and its metabolites. The simultaneous fit of a two-compartment model for VitD3 and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD3 and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD3 and metabolites. This is the first reported population pharmacokinetic modeling of VitD3 and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D3 concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD.

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD ) and its three major metabolites, 25-hydroxyvitamin D (25D ), 1,25-dihydroxyvitamin D (1,25D ), and 24,25-dihydroxyvitamin D (24,25D ), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects ( = 29) were administered one dose of oral VitD (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD and its metabolites. The simultaneous fit of a two-compartment model for VitD and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD and metabolites. This is the first reported population pharmacokinetic modeling of VitD and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD.

A new protein-delivery platform can provide sustained secretion of recombinant human erythropoietin with the use of small, transduced autologous dermal implants. Study patients with end-stage renal disease were found to have maintenance of stable hemoglobin levels. To the Editor: Anemia in patients with end-stage renal disease who are undergoing hemodialysis is caused, in part, by a reduction in or absence of secretion of endogenous erythropoietin. Recombinant human erythropoietin given intravenously has been associated with an increased risk of cardiovascular complications and death, which is considered to be related, at least in part, to the high peak levels of plasma erythropoietin that are achieved after intravenous administration. 1 , 2 Transduced autologous restorative gene therapy (TARGT), a new autologous protein-delivery platform designed to provide sustained secretion of proteins such as recombinant human erythropoietin, uses a small autologous dermal explant . . .