Central Volume Of Distribution Research Articles

Population pharmacokinetics of roxadustat in Japanese dialysis-dependent chronic kidney disease patients with anaemia.

AimsOur objective was to develop a population pharmacokinetic (PK) model to describe roxadustat plasma concentrations in Japanese dialysis‐dependent chronic kidney disease (DD‐CKD) patients with renal anaemia and to identify the covariate factors that affect exposure of roxadustat.MethodsIn total, 367 patients (male, 256; female, 111) contributing 1285 concentration values from 4 clinical studies were analysed using a nonlinear mixed‐effects modelling approach. Candidate covariates included clinical characteristics hypothesized to affect roxadustat clearance and bioavailability, such as demographics, hepatic parameters and concomitant drugs.ResultsThe roxadustat PK data in Japanese DD‐CKD patients with renal anaemia were well described by a 2‐compartment disposition model with first‐order absorption and interindividual variability on clearance, central volume of distribution and absorption rate constant. Age was identified as a significant covariate on clearance. PK profiles of haemodialysis and peritoneal dialysis patients were comparable. Eighty‐two percent of patients were administered at least 1 phosphate binder (PB). The effect of PBs on roxadustat concentration was modelled as a decrease in bioavailability. Staggered administration of PBs reduced the effect on roxadustat bioavailability. The clinical impact of all covariates on roxadustat PK was mild and manageable as the roxadustat dose was titrated based on haemoglobin level and administered starting from a low dose.ConclusionRoxadustat PK in Japanese DD‐CKD patients were successfully described by a population PK model. The identified key covariates included coadministration of PBs on the roxadustat bioavailability and age on clearance of roxadustat.

Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome.

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but the relapse rate remained high and the dosing regimen varied widely. The objective of this study was to characterize rituximab pharmacokinetics (PK) in pediatric patients with FRNS/SDNS, and to investigate the differences in rituximab PK between patients with FRNS/SDNS and other disease populations.Methods: Fourteen pediatric patients received rituximab for FRNS/SDNS treatment were enrolled in a prospective, open-label, single-center PK study. A population PK model of rituximab was developed and validated, and PK parameters were derived for quantitative evaluation.Results: A two-compartment PK model best described the data. Body surface area was the most significant covariate for both central clearance (CL) and apparent central volume of distribution (V1). Patients with FRNS/SDNS exhibited a clinically relevant increase in rituximab CL compared to patient population with non-Hodgkin’s lymphoma (NHL).Conclusion: This pilot study indicated that higher doses or more frequent regimens of rituximab may be required for optimal therapeutic effects in patients with FRNS/SDNS. Further clinical studies with more patients are warranted to confirm this result.

Magnesium sulfate pharmacokinetics after intramuscular dosing in women with preeclampsia

BACKGROUNDCurrent intramuscular magnesium dosing regimens in low and middle-income countries are based on indirect absorption parameters to inform pharmacokinetic and pharmacodynamic response.OBJECTIVETo determine if therapeutic serum magnesium levels are obtained in women with severe preeclampsia receiving intramuscular administration of magnesium sulfate using the Pritchard regimen and to compare the key pharmacokinetic variables to those previously published.STUDY DESIGNSerum magnesium levels were obtained at multiple time points at baseline and after magnesium sulfate administration from women with severe preeclampsia receiving the standard Pritchard regimen for seizure prophylaxis at Bayero University, Kano, Nigeria. The pharmacokinetic profiles were constructed for the study cohort and the updated pharmacokinetic model was compared with the one that was previously published.RESULTSA total of 80 blood samples were collected from 20 women with severe preeclampsia (45 collected before childbirth and 35 collected after childbirth). After 11.5 hours of magnesium sulfate administration, 63% of women in the cohort had serum magnesium levels of ≥2.0 mmol/L. Data from women receiving the Pritchard regimen combined with data from women previously modeled after the receipt of intravenous magnesium sulfate were adequately described using a 2-compartment model with first-order absorption and linear elimination from the central compartment. All structural pharmacokinetic parameters including clearance, central volume of distribution, peripheral volume of distribution, and intercompartment clearance were adjusted for maternal weight, and the clearance was further adjusted for serum creatinine level and antepartum or postpartum status. The simulated pharmacokinetic profiles of the updated pharmacokinetic model and the previously published pharmacokinetic model are similar. In previously published pharmacokinetic modeling, absorption rate constant=0.32 and absolute bioavailability=0.86. In the updated pharmacokinetic model, absorption rate constant=0.45 and absolute bioavailability=0.91.CONCLUSIONThese data support the use of the Pritchard regimen as acceptable to achieve therapeutic serum magnesium levels and support the reported simulation of serum magnesium levels and eclampsia response associated with different intramuscular regimens.

Obesity and anesthetic pharmacology: simulation of target-controlled infusion models of propofol and remifentanil.

The prevalence of obesity is increasing, resulting in an increase in the number of surgeries performed to treat obesity and diseases induced by obesity. The associated comorbidities as well as the pharmacokinetic and pharmacodynamic changes that occur in obese patients make it difficult to control the appropriate dose of anesthetic agents. Factors that affect pharmacokinetic changes include the increase in adipose tissue, lean body weight, extracellular fluid, and cardiac output associated with obesity. These physiological and body compositional changes cause changes in the pharmacokinetic and pharmacodynamic parameters. The increased central volume of distribution and alterations in the clearance of drugs affect the plasma concentration of propofol and remifentanil in the obese population. Additionally, obesity can affect pharmacodynamic properties, such as the 50% of maximal effective concentration and the effect-site equilibration rate constant (ke0). Conducting a simulation of target-controlled infusions based on pharmacokinetic and pharmacodynamic models that include patients that are obese can help clinicians better understand the pharmacokinetic and pharmacodynamic changes of anesthetic drugs associated with this population.

Population pharmacokinetics of belantamab mafodotin, a BCMA-targeting agent in patients with relapsed/refractory multiple myeloma.

Belantamab mafodotin (belamaf) is an antibody–drug conjugate (ADC) targeting B‐cell maturation antigen (BCMA). Nonlinear mixed‐effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine‐maleimidocaproyl‐MMAF (cys‐mcMMAF) after 0.03–4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM‐1, n = 73; DREAMM‐2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys‐mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two‐compartment PopPK model with a time‐varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM‐2 patient was 0.936 L/day with a half‐life of 11.5 days, over time CL was reduced by 28% resulting in a half‐life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys‐mcMMAF concentrations were described with a linear two‐compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio [DAR]) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys‐mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys‐mcMMAF concentration–time profiles in RRMM were well‐described by PopPK models, and exposure was most strongly impacted by disease‐related characteristics.

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.

There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. ClinicalTrials.gov ID: NCT02365272.

Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations.

Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non‐E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non‐Asian subjects. A 2‐compartment model with first‐order absorption, lag time, and first‐order elimination was fitted to the observed data. For the E/SE Asian vs non‐E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non‐E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non‐Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non‐Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration‐time curve. Therefore, the differences in CL/F (area under the concentration‐time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis.

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

Greater Efficacy and Potency of Obinutuzumab Compared with Rituximab in Chronic Lymphocytic Leukemia Patients Confirmed By a Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Model

▪Introduction: In the pivotal CLL11 study (NCT02053610) that compared two CD20-targeting monoclonal antibodies in combination with chlorambucil (Clb) for the treatment of chronic lymphocytic leukemia (CLL), obinutuzumab (GA101; G) was shown to be superior to rituximab (R), with higher rates of complete response and prolongation of progression-free survival (PFS) in elderly CLL patients (pts) with comorbidities. However, the relationship between dose, exposure, and outcome is often complicated by the extent of tumor burden for antibody treatments for which target-mediated elimination is substantial, a case in which drug-binding to the pharmacological target influences drug exposure. Addressing this complexity necessitates the use of mechanistic mathematical models incorporating the extent of changes in pt target burden and its effect on drug disposition. We conducted a retrospective analysis to develop and evaluate a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for comparing drug exposure and clinical outcomes in CLL11.Methods: A semi-mechanistic PK/PD model (Figure 1) was developed for temporal changes in drug and lymphocyte counts in 632 pts who participated in the CLL11 study (325 pts treated with R-Clb and 307 pts with G-Clb). The model features both drug- and system-specific parameters allowing for the direct comparison of key factors that govern the critical responses observed with each antibody. Measurements of serum R concentrations were not available in CLL11. Therefore, R PK data were simulated using a prior population model describing R PK in CLL pts (Li et al. J Clin Pharmacol 2012) and actual dosing information from CLL11 pts. Drug concentrations and lymphocyte counts were analyzed with a nonlinear mixed effects approach using the Stochastic Approximation to Expectation Maximization (SAEM) algorithm in Monolix (version 4.3.3; Lixoft, Orsay, France). Covariate analysis was performed to identify major factors contributing to the inter-individual variability (IIV) in model parameters. The final PK/PD model was used in simulations of alternative dosing amounts and schedules (e.g. R given at the dose of G, G at the dose of R), and time-to-event modeling was used to assess the potential of various model-derived or pt-specific factors to predict PFS.Results: A semi-mechanistic PK/PD model structure was developed for joint modeling of both CD20-targeting agents, and all parameters were estimated with good precision (Table 1), albeit with high IIV, especially for PD parameters. Drug removal due to drug-target binding (kint) was 4.3-fold lower for G than that for R (0.0642 vs. 0.274 nM-1×day-1, p<0.01). The antitumor effect of R did not correlate with this greater clearance, suggesting this antibody loss is likely due to mechanisms not associated with its cytotoxic effects. The coefficient of cell kill (kkill) for G was estimated to be 4.7-fold greater than that for R (0.851 vs. 0.182 day-1, p<0.01), whereas the half-maximal effective concentration (EC50) of G was 15-fold lower (64.5 vs. 962 nM, p<0.01), indicating a significantly greater efficacy and potency compared with R based on the reduction of circulating lymphocytes. Body surface area was identified as a covariate for the IIV of the central drug volume of distribution. Model-based simulations suggest that G exhibits superior efficacy, regardless of alternative dosing schedules, as compared with R. Finally, time-to-progression analysis revealed that model-predicted antibody concentration and the percent reduction from baseline in minimal residual disease (MRD) were predictors of PFS in CLL pts.Conclusion: A comparative population-based semi-mechanistic PK/PD model was developed for analyzing exposure-outcome relationships for R and G in CLL11. Parameters associated with antibody elimination from the system indicated a faster rate of target-mediated clearance for R, whereas greater efficacy and potency of G were identified from differences in drug-specific PD parameters. A time-to-event model suggested that serum drug concentrations and percent reduction from baseline in MRD are predictors of PFS in CLL pts. [Display omitted] DisclosuresKamisoglu:Roche: Other: CLL11 is sponsored by F. Hoffmann-La Roche Ltd in collaboration with the GCLLSG and Genentech, Inc. Third-party editorial support, under the direction of Dr Kamisoglu, was provided by Scott Malkin of Gardiner-Caldwell Communications, and funded by Roche. Phipps:Roche: Equity Ownership. Jamois:Roche: Employment, Other: GALLIUM was sponsored by F. Hoffmann-La Roche Ltd.. Buchheit:Roche: Employment. Meneses-Lorente:Roche Products Ltd: Employment. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Wagg:F. Hoffmann-La Roche Ltd: Employment. Mager:Enhanced Pharmacodynamics, LLC: Employment, Equity Ownership; Roche: Research Funding.

Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

BackgroundThe aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies.MethodsWe conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens.ResultsPlasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall.ConclusionA dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

Population pharmacokinetics of oral levofloxacin in healthy volunteers and dosing optimization for multidrug-resistant tuberculosis therapy.

Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32Lh-1 (22.6%), apparent central volume of distribution 35.8L (45.2%), apparent peripheral volume of distribution 39.7L, intercompartmental clearance 40.6Lh-1 (43.8%), absorption rate constant 7.45h-1 (150%), mean absorption transit time 0.355h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5mg L-1 , while a dose of 1500mg was required for strains with an MIC of 1mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.

Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates

Introduction: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. Methods: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. Results: The median (IQR) central volume of distribution (Vd_c) and clearance (CL) for sufentanil were 4.7 (4.1–5.4) L/kg and 0.651 (0.433–0.751) L/h/kg, respectively. Linear regression models showed relationship between Vd_c (L) and GA (r² = 0.3436; p = 0.0452) as well as BW (r² = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78–2.48) μg/kg and 0.29 (95% CI: 0.22–0.37) μg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. Discussion/Conclusion: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

Population pharmacokinetics and exposure-response analysis of tigecycline in patients with hospital-acquired pneumonia.

Tigecycline has been widely used to treat hospital-acquired pneumonia (HAP) off-label since it is effective against a wide range of multidrug-resistant bacteria. However, no recommended dosage for this indication has been evaluated, resulting in possible inadequate treatment. The aims of this study are to establish the population pharmacokinetic (PPK) model of tigecycline in Chinese patients with HAP, as well as to evaluate the exposure-response relationship for the treatment of HAP with multidrug-resistant gram-negative bacteria. A PPK analysis of tigecycline was conducted on pooled data from 328 blood samples obtained from 89 patients with HAP. Tigecycline plasma concentrations were measured by a two-dimensional liquid chromatographic system and the data were analysed using Phoenix NLMETM software. Exposure-response analyses for efficacy were performed based on the data from 79 HAP patients with multidrug-resistant gram-negative infections. Classification and regression tree and logistic regression analyses were employed to identify which pharmacokinetic-pharmacodynamic (PK-PD) indices and magnitudes were the significant predictors of tigecycline efficacy. A two-compartment model with zero-order absorption and first-order elimination adequately described the data. A larger body weight was associated with increased central volume of distribution and clearance (P<.005), and increased age, baseline creatinine concentration and aspertate aminotransferase were associated with decreased clearance (P<.005). The AUC0-12h ×V/MIC ratio, APACHEII score and combined Pseudomonas aeruginosa infection are the strong predictors for tigecycline clinical response. Classification and regression tree analyses indicated that the combination of APACHEII score < 24 and AUC0-12h ×V/MIC ratio≥100 was associated with clinical success. The proposed PPK model may serve as the basis for estimating tigecycline exposure for PK-PD analyses, and the PK-PD index and magnitude found in this study could be used for designing proper dosage regimens of tigecycline.

English

An alteration of pharmacokinetics (PK) due to pathophysiological changes in patients with critical illnesses have the impact on the drug levels in plasma, consequently affecting the achievement of pharmacodynamics (PD) targets of antibiotics. The objectives of this study were (i) to determine the population PK, and (ii) to assess the probability of target attainment (PTA) of ertapenem in patients with critical conditions. The study examined the population PK of ertapenem using NONMEM and performed the assessment of the PTAs of achieving 40 and 80% of the time that the free drug level exceeds over the MIC (fT&gt;MIC). The central and peripheral volumes of distribution were 49 (with the %CV of 67.10) and 91.90 (with the %CV of 78.90) L, respectively, and total clearance of ertapenem was 15.40 (with the %CV of 46.80) L/h. Our PD analysis for achieving a target of 40% fT&gt;MIC in patients with normal renal function, the dosing of 1 g once daily can cover a MIC of 0.5 mg/L and for a higher minimum inhibitory concentration (MIC) of 1 mg/L, the dosing should be increased to 2 g once daily. Moreover, the achievements of PTAs in patients with lower GFRs were greater than those of PTAs in patients with higher GFRs. In conclusion, higher than maximum recommended dosing of ertapenem may be required for achieving the PD targets in septic patients with critical illnesses; however, in renal impaired patients the required dosage regimens may be lower than recommended dosing. Key words: Pharmacokinetics, pharmacodynamics, ertapenem, sepsis, Monte Carlo simulation.

Pharmacokinetics of Selinexor: The First-in-Class Selective Inhibitor of Nuclear Export.

The functionality of many tumor suppressor proteins (TSPs) and oncoprotein transcript RNAs largely depend on their location within the cell. The exportin 1 complex (XPO1) transports many of these molecules from the nucleus into the cytoplasm, thereby inactivating TSPs and activating oncoprotein transcript RNAs. Aberrations of these molecules or XPO1 can increase this translocation process, leading to oncogenesis. Selinexor is a selective inhibitor of nuclear export and is an active agent in various malignancies. It is currently approved for relapsed or refractory diffuse large B-cell lymphoma as well as multiple myeloma. Following oral administration, selinexor exhibits linear and time-independent pharmacokinetics (PK) across a wide dose range, with moderately rapid absorption (time to reach maximum concentration [Tmax] 2-4 h) and moderate elimination (half-life [t½] 6-8h). Selinexor PK observed among patients with various solid tumors and hematologic malignancies is consistent irrespective of disease. Population PK analyses demonstrated the PK of selinexor is well-described by a two-compartment model, with significant relationships for body weight on apparent clearance and apparent central volume of distribution, and sex on apparent clearance, which result in clinically non-relevant changes in exposure. These analyses also suggested selinexor PK are not significantly impacted by various concomitant medications and organ dysfunction (hepatic/renal). The time course of selinexor PK appears similar between pediatric and adult patients, although higher exposures have been observed among pediatric patients relative to adults administered similar milligrams per meter squared (mg/m2) doses of selinexor.

Piperacillin-Tazobactam in Intensive Care Units: A Review of Population Pharmacokinetic Analyses.

Piperacillin-tazobactam is a potent β-lactam/β-lactamase inhibitor antibiotic commonly prescribed in the intensive care unit setting. Admitted patients often show large variability in treatment response due to multiple pathophysiological changes present in this population that alter the drug's pharmacokinetics. This review summarizes the population pharmacokinetic models developed for piperacillin-tazobactam and provides comprehensive data on current dosing strategies while identifying significant covariates in critically ill patients. A literature search on the PubMed database was conducted, from its inception to July 2020. Relevant articles were retained if they met the defined inclusion/exclusion criteria. A total of ten studies, published between 2009 and 2020, were eligible. One- and two-compartment models were used in two and eight studies, respectively. The lowest estimated piperacillin clearance value was 3.12 L/h, and the highest value was 19.9 L/h. The estimations for volume of distribution varied between 11.2 and 41.2 L. Tazobactam clearance values ranged between 5.1 and 6.78 L/h, and tazobactam volume of distribution values ranged between 17.5 and 76.1 L. The most frequent covariates were creatinine clearance and body weight, each present in four studies. Almost all studies used an exponential approach for the interindividual variability. The highest variability was observed in piperacillin central volume of distribution, at a value of 75.0%. Simulations showed that continuous or extended infusion methods performed better than intermittent administration to achieve appropriate pharmacodynamic targets. This review synthesizes important pharmacokinetic elements for piperacillin-tazobactam in an intensive care unit setting. This will help clinicians better understand changes in the drug's pharmacokinetic parameters in this specific population.

Model-Based Estimation of Iohexol Plasma Clearance for Pragmatic Renal Function Determination in the Renal Transplantation Setting

BackgroundIohexol plasma clearance-based glomerular filtration rate (GFR) determination provides an accurate method for renal function evaluation. This technique is increasingly advocated for clinical situations that dictate highly accurate renal function assessment, as an alternative to conventional serum creatinine-based methods with limited accuracy or poor feasibility. In the renal transplantation setting, this particularly applies to living renal transplant donor eligibility screening, renal transplant function monitoring and research purposes. The dependency of current iohexol GFR estimation techniques on extensive sampling, however, has limited its clinical application. We developed a population pharmacokinetic model and limited sampling schedules, implemented in the online InsightRX precision dosing platform, to facilitate pragmatic iohexol GFR assessment.MethodsIohexol concentrations (n = 587) drawn 5 min to 4 h after administration were available from 67 renal transplant recipients and 41 living renal transplant donor candidates with measured iohexol GFRs of 27–117 mL/min/1.73 m2. These were split into a model development (n = 72) cohort and an internal validation (n = 36) cohort. External validation was performed with 1040 iohexol concentrations from 268 renal transplant recipients drawn between 5 min and 4 h after administration, and extended iohexol curves up to 24 h from 11 random patients with impaired renal function. Limited sampling schedules based on one to four blood draws within 4 h after iohexol administration were evaluated in terms of bias and imprecision, using the mean relative prediction error and mean absolute relative prediction error. The total deviation index and percentage of limited sampling schedule-based GFR predictions within ± 10% of those of the full model (P10) were assessed to aid interpretation.ResultsIohexol pharmacokinetics was best described with a two-compartmental first-order elimination model, allometrically scaled to fat-free mass, with patient type as a covariate on clearance and the central distribution volume. Model validity was confirmed during the internal and external validation. Various limited sampling schedules based on three to four blood draws within 4 h showed excellent predictive performance (mean relative prediction error < ± 0.5%, mean absolute relative prediction error < 3.5%, total deviation index < 5.5%, P10 > 97%). The best limited sampling schedules based on three to four blood draws within 3 h showed reduced predictive performance (mean relative prediction error < ± 0.75%, mean absolute relative prediction error < 5.5%, total deviation index < 9.5%, P10 ≥ 85%), but may be considered for their enhanced clinical feasibility when deemed justified.ConclusionsOur online pharmacometric tool provides an accurate, pragmatic, and ready-to-use technique for measured GFR-based renal function evaluation for clinical situations where conventional methods lack accuracy or show limited feasibility. Additional adaptation and validation of our model and limited sampling schedules for renal transplant recipients with GFRs below 30 mL/min is warranted before considering this technique in these patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-00998-z.

Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1\u201318 Years

Vancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received >1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function.

Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia.

Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications. The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine. Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine. A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasmaconcentration-timecurve (AUC) and maximum plasma concentration (Cmax) was within ± 25%. The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.

Selinexor population pharmacokinetic and exposure-response analyses to support dose optimization in patients with diffuse large B-cell lymphoma.

Characterize the population PK and exposure-response (ER) relationships of selinexor in patients with diffuse large B-cell lymphoma (DLBCL) (efficacy endpoints) or other non-Hodgkin's lymphoma (NHL) patients (safety endpoints) to determine the optimal dose in patients with DLBCL. This work included patients from seven clinical studies, with 800 patients for PK, 175 patients for efficacy and 322 patients for safety analyses. Logistic regression models and Cox-regression models were used for binary and time-to-event endpoints, respectively. Model-based simulations were performed to justify dose based on balance between efficacy and safety outcome. Selinexor pharmacokinetics were well-described by a two-compartment model with body weight as a significant covariate on clearance and central volume of distribution and gender on clearance. Overall response rate (ORR) in patients with DLBCL increased with day 1 Cmax and decreased in patients with higher baseline tumor size (p < 0.05). Significant exposure-safety relationships (p < 0.05) in NHL patients were identified for the frequency of the following safety endpoints: dose modifications, decreased appetite Grade ≥ 3 (Gr3+), fatigue Gr2+, vision blurred Gr1+, and vomiting Gr2+. Similar exposure-safety relationships were found for time-to-onset of the adverse events. Simulations of the safety and efficacy ER models suggested that, compared to a starting dose of 60mg twice weekly (BIW), a 40mg BIW regimen resulted in an absolute decrease in AE probabilities between 1.9 and 5.3%, with a clinically significant absolute efficacy decrease of 4.7% in ORR. The modeling results support that 60mg BIW is the optimal dose in patients with DLBCL.