Estimation Of Clearance Research Articles

Population Pharmacokinetic Model of Iohexol in Dogs to Estimate Glomerular Filtration Rate and Optimize Sampling Time.

Monitoring iohexol plasma clearance is considered a useful, reliable, and sensitive tool to establish glomerular filtration rate (GFR) and early stages of kidney disease in both humans and veterinary medicine. The assessment of GFR based on iohexol plasma clearance needs repeated blood sampling over hours, which is not easily attainable in a clinical setting. The study aimed to build a population pharmacokinetic (Pop PK) model to estimate iohexol plasma clearance in a population of dogs and based on this model, to indicate the best sampling times that enable a precise clearance estimation using a low number of samples. A Pop PK model was developed based on 5 iohexol plasma samples taken from 5 to 180 minutes (min) after an intravenous iohexol nominal dose of 64.7 mg/kg from 49 client-owned dogs of different breeds, sexes, ages, body weights, and clinical conditions (healthy or presenting chronic kidney disease CKD). The design of the best sampling times could contain either 1 or 2 or 3 sampling times. These were discretized with a step of 30 min between 30 and 180 min. A two-compartment Pop PK model best fitted the data; creatinine and kidney status were the covariates included in the model to explain a part of clearance variability. When 1 sample was available, 90 or 120 min were the best sampling times to assess clearance for healthy dogs with a low creatinine value. Whereas for dogs with CKD and medium creatinine value, the best sampling time was 150 or 180 min, for CKD dogs with a high creatinine value, it was 180 min. If 2 or 3 samples were available, several sampling times were possible. The method to define the best sampling times could be used with other Pop PK models as long as it is representative of the patient population and once the model is built, the use of individualized sampling times for each patient allows to precisely estimate the GFR.

Population Pharmacokinetics of Lithium in Young Pediatric Patients With Intellectual Disability.

Background: Lithium is a well-established treatment for bipolar disorders and has been shown to be neuroprotective, and thus low doses might be useful for the treatment of childhood brain injury and neurological sequelae. However, pharmacokinetic (PK) data in children are limited. This study was to investigate the PKs after oral administration of low-dose lithium carbonate in young children with intellectual disability. Methods: Fifty-two children with intellectual disability aged 4–10 years old were enrolled. A series of blood samples were collected after a single-dose administration of lithium carbonate. The serum lithium concentration was measured using a validated ion chromatography assay, and the PK concentration data were modeled using a nonlinear mixed effect model in the NONMEM program. Results: The lithium concentration over time was adequately described by a two-compartment disposition, with a transient absorption and first-order elimination process. The inclusion of body weight as an allometric factor significantly improved the model fit, but age and gender were not associated with the PKs of lithium. The clearance, central volume, inter-compartmental clearance, and peripheral volume estimates from the final population PK model were 0.98 L/h, 13.1 L, 0.84 L/h, and 8.2 L for children with a body weight of 20 kg. The model evaluation suggested that there is no obvious discrepancy between the observations and predictions in the proposed model. A visual predictive check demonstrated the good predictive performance of the final model. Conclusions: The lithium PK properties in young children were similar to those in older children and adults. The proposed model can be used for further PK/PD analysis to optimize the dosage regimen of lithium in children.

SUB-CLINICAL DAMAGE TO THE TARGET ORGANS (TOD) IN HYPERTENSIVE PATIENTS, ABOUT 300 PATIENTS

Objective: HTA is considered to be a silent killer. TOD is an indicator of cardiovascular risk in people with hypertension. The main objective of our study is to describe the sub-clinical TOD in hypertensive patients. Design and method: This is a descriptive study, conducted between October 2016 and October 2019. It included all asymptomatic hypertensive patients over the age of 35 of both sexes. Screening for infraclinical cardiac, vascular and renal damage is carried out with; the evaluation of the left ventricular hypertrophy (LVH) ultrasound and electric. Intima media thickness measurement by 2D carotid ultrasound and screening and evaluation of plaques. The measurement of pulsed pressure. Measuring the ABI for obliterating arterial disease. And finally, the estimate of urinary albumin excretion (UEA) and creatinine clearance according to MDRD. Results: 300 patients included in our series, these are 120 men and 180 women. The average age is 59.75 years. The prevalence of TOD is estimated at 72.3%, the prevalence of electrical LVH is 17.3%, the ultrasound LVH is 29%. Carotid hypertrophy is observed in 34.9% and the presence of stenotic plaques affect 9.1% of patients AOMI is found in 9%. Pathological pulsed pressure is found in 34.3%. UAE is pathological in 23.30% of our patients for A2 and 5.7% for A3. The creatinine clearance is less than 60 ml / min in 11%. The main independent risk factors associated with TOD are the value of SBP and Age. Pulse pressure> 60 mmHg is associated with all TOD and the IMT is correlated with all screening tests for TOD. The SCORE score is predictive only for carotid lesions, it is not predictive for LVH or albuminuria. The SCORE score is not very predictive for AOMI and renal failure. Conclusions: Subclinical TOD is frequent in our series. The major modifiable independent risk factor is the value of SBP. Special attention to pulse pressure as a cardiovascular risk factor and marker of arterial stiffness A strategy for screening for target organ damage coupled with effective therapy targeting SBP is the only way to prevent cardiovascular, neurovascular and renal complications.

Limited sampling strategies for accurate determination of extended half-life factor VIII pharmacokinetics in severe haemophilia A patients.

Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies. Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose+peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population. The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

Creatinine Assessment in Non-Steady-State Conditions: A Critical Review.

To discuss methods for the assessment of creatinine clearance (Clcr) when serum creatinine (SCr) is not at steady state in order to estimate kidney function and apply the estimate to kidney function staging for clinical assessment or drug dosing. A PubMed search was conducted from 1976 to mid-January 2021 with other articles identified through review of bibliographies of retrieved articles and citations in Scopus. Articles assessing Clcr under non-steady-state conditions and studies evaluating predictive equations were selected. When SCr is systematically changing (ie, trending up or down), kinetic methods to estimate Clcr are appropriate. Estimates from kinetic methods should be individual based and not indexed to body surface area, and careful monitoring is required to confirm predictions as the situation evolves. Standard methods intended for steady-state conditions should not be used to estimate Clcr in patients with unstable SCr. Creatinine continues to be a monitoring parameter of choice and is an important variable in all the commonly used equations for estimating Clcr and most important for estimating glomerular filtration rate. However, standard methods of estimating Clcr for medication dosing are not accurate under non-steady-state conditions. The methods for kinetic clearance estimation and standards methods for clearance estimation, such as the Cockcroft-Gault equation, are mutually exclusive. There are no benefits of using the kinetic method in patients with stable SCr concentrations, and standard equations are not appropriate with unstable SCr concentrations.

Effect of race and glucuronidation rates on the relationship between nicotine metabolite ratio and nicotine clearance.

To investigate if the nicotine metabolite ratio (NMR, the ratio of nicotine metabolites 3'-hydroxycotinine/cotinine) is a reliable phenotypic biomarker for nicotine clearance across races, and as a function of differences in the rate of nicotine, cotinine and 3'-hydroxycotinine glucuronidation and UGT genotypes. Participants [Caucasians (Whites), African Americans (Blacks) and Asian-Americans (Asians)] received an oral solution of deuterium-labeled nicotine and its metabolite cotinine. Plasma and saliva concentrations of nicotine and cotinine were used to determine oral clearances. Rates of glucuronidation were assessed from urine glucuronide/parent ratios, and UGT2B10 and UGT2B17 genotypes from DNA. Among the 227 participants, 96 (42%) were White, 67 (30%) Asian and 64 (28%) Black. Compared to the other two races, Whites had higher nicotine and cotinine total oral clearance, Blacks had lower nicotine and cotinine glucuronidation rates and Asians had lower 3'-hydroxycotinine glucuronidation rates. A strong positive correlation (correlations coefficients 0.77-0.84; P < 0.001) between NMR and nicotine oral clearance was found for all three races, and NMR remained a strong predictor for the nicotine oral clearance while adjusting for race, sex and age. Neither the metabolite glucuronidation ratios nor the UGT genotypes had significant effects on the ability of NMR to predict nicotine oral clearance. NMR appears to be a reliable phenotypic biomarker for nicotine clearance across races, glucuronidation phenotypes and genotypes. Racial differences in the relationships between NMR, smoking behaviors and addiction are unlikely to be related to an inadequate estimation of nicotine clearance on the basis of NMR.

Metformin doses to ensure efficacy and safety in patients with reduced kidney function.

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was <5% for most doses and kidney function levels. The lower dose of 500 mg daily was required to maintain concentrations below the safety limits for patients with an eGFR of 15–29 mL/min. Our analysis suggests that a maximum daily dose of 2250, 1700, 1250, 1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b and 4, respectively, will provide a reasonable probability of achieving efficacy and safety. Our results support the cautious of use metformin at appropriate doses in patients with impaired kidney function.

Classification Tree Analysis Based On Machine Learning for Predicting Linezolid-Induced Thrombocytopenia.

Linezolid-induced thrombocytopenia is related to linezolid exposure, baseline platelet count and patient background. Although the relationship usually reflects the time of onset of thrombocytopenia, if the platelet maturation process is taken into account, the platelet decrease can be considered to have started at the beginning of treatment. To predict linezolid-induced thrombocytopenia, classification and regression tree (CART) analysis based on machine learning has been applied to identify predictive factors and cutoff values. We examined 74 patient data with or without linezolid-induced thrombocytopenia. Linezolid concentration and platelet count change, baseline platelet count, age, body weight and creatinine clearance estimate were evaluated as predictive factors for linezolid-induced thrombocytopenia. CART analysis selected the final tree containing two cutoff values: a platelet count reduction to less than 2.3% from baseline at 96h after the initial dose and a linezolid concentration greater than or equal to 13.5mg/L at 96h after the initial dose. The targets for therapeutic intervention were concluded to be the linezolid concentration and the platelet change from baseline at 96h after the initial dose. These cutoff values occur prior to the onset of thrombocytopenia and should be monitored to avoid linezolid-induced thrombocytopenia.

Dolutegravir pharmacokinetics during co-administration with either artemether/lumefantrine or artesunate/amodiaquine.

In sub-Saharan Africa, artemisinin-containing therapies for malaria treatment are regularly co-administered with ART. Currently, dolutegravir-based regimens are recommended as first-line therapy for HIV across most of Africa. To investigate the population pharmacokinetics of dolutegravir during co-administration with artemether/lumefantrine or artesunate/amodiaquine, two commonly used antimalarial therapies. We developed a population pharmacokinetic model of dolutegravir with data from 26 healthy volunteers in two Phase 2 studies with a total of 403 dolutegravir plasma concentrations at steady state. Volunteers received 50 mg of dolutegravir once daily alone or in combination with standard treatment doses of artemether/lumefantrine (80/480 mg) or artesunate/amodiaquine (200/540 mg). A two-compartment model with first-order elimination and transit compartment absorption best described the concentration-time data of dolutegravir. Typical population estimates for clearance, absorption rate constant, central volume, peripheral volume and mean absorption transit time were 0.713 L/h, 1.68 h-1, 13.2 L, 5.73 L and 1.18 h, respectively. Co-administration of artemether/lumefantrine or artesunate/amodiaquine increased dolutegravir clearance by 10.6% (95% CI 4.09%-34.5%) and 26.4% (95% CI 14.3%-51.4%), respectively. Simulations showed that simulated trough concentrations of dolutegravir alone or in combination with artemether/lumefantrine or artesunate/amodiaquine are maintained above the dolutegravir protein-adjusted IC90 of 0.064 mg/L for more than 99% of the individuals. Dolutegravir dose adjustments are not necessary for patients who are taking standard 3 day treatment doses of artemether/lumefantrine or artesunate/amodiaquine.

Development of an Automated Minimum Foot Clearance Measurement System: Proof of Principle.

Over half of older adult falls are caused by tripping. Many of these trips are likely due to obstacles present on walkways that put older adults or other individuals with low foot clearance at risk. Yet, Minimum Foot Clearance (MFC) values have not been measured in real-world settings and existing methods make it difficult to do so. In this paper, we present the Minimum Foot Clearance Estimation (MFCE) system that includes a device for collecting calibrated video data from pedestrians on outdoor walkways and a computer vision algorithm for estimating MFC values for these individuals. This system is designed to be positioned at ground level next to a walkway to efficiently collect sagittal plane videos of many pedestrians’ feet, which is then processed offline to obtain MFC estimates. Five-hundred frames of video data collected from 50 different pedestrians was used to train (370 frames) and test (130 frames) a convolutional neural network. Finally, data from 10 pedestrians was analyzed manually by three raters and compared to the results of the network. The footwear detection network had an Intersection over Union of 85% and was able to find the bottom of a segmented shoe with a 3-pixel average error. Root Mean Squared (RMS) errors for the manual and automated methods for estimating MFC values were 2.32 mm, and 3.70 mm, respectively. Future work will compare the accuracy of the MFCE system to a gold standard motion capture system and the system will be used to estimate the distribution of MFC values for the population.

Pharmacokinetic Modelling of Human Recombinant Protein, p75ECD-Fc: A Novel Therapeutic Approach for Treatment of Alzheimer's Disease, in Serum and Tissue of Sprague Dawley Rats.

p75ECD-Fc is a novel antagonist of toxic amyloid beta protein and other neurodegenerative factors with potential for the treatment of Alzheimer's disease (AD). Preclinical studies showed that it can alleviate the AD pathologies in animal models of dementia. In a previous paper, we used non-compartmental pharmacokinetic analysis to obtain preliminary pharmacokinetic data for p75ECD-Fc in Sprague Dawley (SD) rats. We also studied the tissue distribution in terms of drug metabolism that helped us to understand possible mechanisms of action. Here, we aim to develop population pharmacokinetic models that can describe the pharmacokinetics of p75ECD-Fc in serum and tissues. p75ECD-Fc was delivered to SD rats via two routes (intravenous and subcutaneous) at a single dose of 3 mg/kg (n = 15). Blood (n = 12) and tissue samples (n = 10-15) were then separated at different time points for a total duration of 42 days post dosage. The concentration of p75ECD-Fc in serum and tissues was measured using an enzyme-linked immunosorbent assay. Data were best fitted to a 2-compartment model with linear elimination kinetics. The population parameter estimates for clearance, and volume of central and peripheral compartments were 0.000176 L/h, 0.0145 L and 0.0263 L, respectively. The presence of anti-drug antibodies was added to the final model as a covariate on clearance. The subcutaneous bioavailability was estimated to be 53.5% with a first-order absorption rate constant of 0.00745 1/h. By modeling of individual tissue concentrations, p75ECD-Fc was found to exhibit modest tissue distribution with estimated tissue/plasma partition coefficients (R) ranging from 0.004 to 0.2. This is the first report of a pharmacokinetic model for p75ECD-Fc and these results may facilitate the ongoing development of p75ECD-Fc and translation to clinical studies.

Incidence and Prevalence of Trichomonas vaginalis Infection Among Persons Aged 15 to 59 Years: United States, 2018.

Trichomonas vaginalis (TV) is a sexually transmitted parasite associated with multiple adverse outcomes in women. Estimating TV incidence is challenging because of its largely asymptomatic presentation. Per-capita prevalence was estimated using the National Health and Nutrition Examination Survey, 2013 to 2018. Incidence was estimated using ordinary differential equations assuming static incidence at steady state and fit using Bayesian techniques. Model inputs included estimates of proportion of asymptomatic cases, natural clearance, and time to symptomatic treatment seeking. Posterior distributions were drawn, and uncertainty was reported, from 25th (Q1) to 75th (Q3) percentiles. Aggregated measures were estimated by combining component distributions. Among 15- to 59-year-olds in 2018, the number of prevalent TV infections was 2.6 (Q1, 2.4; Q3, 2.7) million overall, 470,000 (Q1, 414,000; Q3, 530,000) among men, and 2.1 (Q1, 2.0; Q3, 2.2) million among women; the numbers of incident infections were 6.9 (Q1, 6.2; Q3, 7.6) million, 3.3 (Q1, 2.8; Q3, 3.8) million, and 3.5 (Q1, 3.1; Q3, 4.0) million among all persons, men, and women, respectively. Persons aged 15 to 24 years comprised 15.6% and 16.3% of all prevalent and incident infections, respectively; prevalence and incidence in both sexes increased with age. Incidences in both sexes were highly dependent on estimates of natural clearance, which were based on few data. Prevalence and incidence of TV are substantial in the United States, particularly among those 25 years or older. Although estimated prevalence is higher in women, estimated incidence is similar in men and women. Data on key parameters of TV infection are limited; future research should focus on clarifying the natural history of TV.

Pharmacokinetics of Roxadustat: A Population Analysis of 2855 Dialysis- and Non-Dialysis-Dependent Patients with Chronic Kidney Disease

Roxadustat is a novel, small-molecule, first-in-class therapeutic that stimulates erythropoiesis by inhibiting hypoxia-inducible factor prolyl hydroxylase enzymes. This agent (roxadustat) is in clinical development for the treatment of anemia in patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) chronic kidney disease. A population pharmacokinetic analysis was undertaken to evaluate the effect of intrinsic and extrinsic factors on roxadustat pharmacokinetics. Non-linear mixed-effects models implemented in NONMEM software were fitted to 8209pharmacokinetic samples from 2855 DD and NDD subjects enrolled in four phase III studies with roxadustat dose concentrations of 20-400 mg as orally administered tablets. Effects of intrinsic and extrinsic factors were evaluated using a stepwise covariate modeling procedure in combination with the full covariate approach, and defined no-effect boundaries for exposure were based on the difference in exposure between 70 and 100 mg of roxadustat (i.e., - 30%, + 43%). A two-compartment model with first-order absorption adequately described roxadustat pharmacokinetics, with parameter estimates (relative standard error) for apparent clearance of 1.1 (0.0223) L/h in NDD subjects, and apparent central and peripheral volumes of distribution of 14.9 (0.0278) L and 9.5 (0.0872) L, respectively. Stepwise covariate modeling identified bodyweight, dialysis status, race, and dose as statistically significant covariates on apparent clearance, and bodyweight, sex, and albumin as statistically significant covariates on apparent central volume of distribution. However, the effects of these covariates did not result in roxadustat area under the curve or maximum plasma concentration changes outside of the defined no-effect boundaries. The effects of concomitant oral iron, clopidogrel, and staggered sevelamer, calcium carbonate, or calcium acetate were investigated using a full covariate approach but did not result in roxadustat area under the curve or maximum plasma concentration changes outside of the defined no-effect boundaries. A population pharmacokinetic model was developed for the pharmacokinetics of roxadustat in the target population. None of the investigated intrinsic or extrinsic factors resulted in a significant change in roxadustat exposure outside of the defined no-effect boundaries.

Estimation of Tacrolimus Clearance in Saudi Adult Kidney Transplant Recipients

Tacrolimus is commonly used in adult kidney transplant patients. Only few studies have so far described the pharmacokinetics of tacrolimus in the Saudi population. Thus, the goal of this study is to determine the population pharmacokinetics of tacrolimus in Saudi adult kidney transplant recipients and to identify the factors that explain variability. We performed a retrospective chart review of adult patients who received oral tacrolimus at two centers. We developed the population pharmacokinetic models using Monolix 4.4. The factors screened for influence on these parameters were weight, age, gender, liver function tests, and creatinine clearance. The analysis included a total of 149 tacrolimus plasma concentrations from 139 patients. A one-compartment open model with linear absorption and elimination adequately described the data. The average parameter estimates for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 9.1 L/h and 912 L, respectively. The interindividual variabilities (coefficients of variation) in CL/F and V/F were 20% and 18%, respectively. Aspartate aminotransferase was identified to be the main covariate that influences tacrolimus CL/F. In conclusion, the population pharmacokinetic model of tacrolimus was established and a significant covariate of the model was identified. These findings offer a rationale for the personalization of tacrolimus dosing regimens. Further studies are required to understand the factors that may influence the pharmacokinetics of tacrolimus and assist in drug dosage decisions.

A retrospective study comparing creatinine clearance estimation using different equations on a population-based cohort

&lt;abstract&gt; &lt;p&gt;Renal elimination is an important part of drugs' excretion. At the same time, renal function can be impaired as a side effect of medication, particularly during prolonged treatments. Thus, the assessment of patients' renal function is of major consequence, especially in cases where the therapeutic regimen is adjusted taking into consideration renal clearance. Serum creatinine concentration is the most common indicator of renal clearance, since the most accurate indicator, glomerular filtration rate (GFR), is not easily measured. Using equations developed over the last decades, creatinine clearance (CL&lt;sub&gt;Cr&lt;/sub&gt;) is readily estimated taking into account patients' biological sex, age, body composition, and sometimes race. In this work, differences in estimated CL&lt;sub&gt;Cr&lt;/sub&gt; between different equations were studied and the influence of some patients' characteristics evaluated. Data collected from 82 inpatients receiving antibiotic therapy was analyzed and CL&lt;sub&gt;Cr&lt;/sub&gt; was estimated using a total of 12 equations. Patients were stratified according to their sex, age, and body composition to shed some light on the impact of these parameters in the estimations of renal function. More variability between estimation methods was highlighted (a) in patients between 51 and 60 years old, (b) within the normal body mass index group, and (c) in patients with serum creatinine levels below normal criteria. Furthermore, the Cockcroft-Gault equation considering lean body weight produced lower estimated CL&lt;sub&gt;Cr&lt;/sub&gt; in almost all groups.&lt;/p&gt; &lt;/abstract&gt;

Physiologically Based Pharmacokinetics of Lysosomotropic Chloroquine in Rat and Human.

A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human concentration versus time data. The PBPK model in rat featured plasma and red blood cell (RBC) concentrations, extensive and apparent nonlinear tissue distribution, fitted hepatic and renal intrinsic clearances, and a plasma half-life of about 1 day. Tissue-to-plasma CQ ratios at 50 hours after dosing were highest in lung, kidney, liver, and spleen (182-318) and lower in heart, muscle, brain, eye, and skin (11-66). The RBC-to-plasma ratio of 11.6 was assumed to reflect cell lipid partitioning. A lysosome-based extended model was used to calculate subcellular CQ concentrations based on tissue mass balances, fitted plasma, interstitial and free cytosol concentrations, and literature-based pH and pKa values. The CQ tissue component concentrations ranked as follows: lysosome > > acidic phospholipid > plasma = interstitial = cytosol ≥ neutral lipids. The extensive lysosome sequestration appeared to change over time and was attributed to lowering pH values caused by proton pump influx of hydrogen ions. The human-to-rat volume of distribution (Vss) ratio of 7 used to scale rat tissue partitioning to human along with estimation of hepatic clearance allowed excellent fitting of oral-dose PK (150-600 mg) of CQ with a 50-day half-life in humans. The prolonged PK of chloroquine was well characterized for rat and human with this PBPK model. The calculated intratissue concentrations and lysosomal effects have therapeutic relevance for CQ and other cationic drugs. SIGNIFICANCE STATEMENT: Sequestration in lysosomes is a major factor controlling the pharmacokinetics and pharmacology of chloroquine and other cationic drugs. This report provides comprehensive physiologic modeling of chloroquine distribution in tissues and overall disposition in rat and human that reveals expected complexities and inferences related to its subcellular association with various tissue components.

Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures.

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration–time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing.

Inter-lobe clearance estimation for twin-screw rotor pairs with point-meshing features

In practical production, it is impossible even to measure the inter-lobe (meshing) clearance of a screw rotor pair. However, understanding of the clearance distribution is essential since it is a major leakage path which greatly affects the twin-screw pump performance. Previous publications did not disclose explicit detail on how to calculate the meshing clearance for screw rotor pairs with point-meshing features. Therefore, this study proposes a meshing clearance calculation method for screw rotor pairs with point-meshing features. The complex meshing clearance can be simply determined by calculating the shortest distance between two normal-rack profiles generated using point-enveloping principle. Clearance distributions are much more intelligible to be exhibited on a 3-D contact line and the rotor profile. Due to its immeasurability in practice, the adaptability and the solution accuracy of the proposed numerical method are verified by applications on different rotor profiles and comparisons with measured results from a 3-D CAD model. The meshing clearance in a variable-pitch screw rotor pair and the clearance adjustability are also illustrated through the proposed examples.

CPX-351 Population Pharmacokinetics in Pediatric and Adult Patients with Acute Myeloid Leukemia (AML)

CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a 1:5 synergistic ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Recently, CPX-351 was used in pediatric patients (pts) with relapsed AML (JCO 2020, ASH 2019, ASH 2018). A population pharmacokinetic (PK) analysis of plasma concentrations of cytarabine and daunorubicin following IV administration of CPX-351 was performed to assess sources of variability in PK and to determine if age-based dose adjustments may be warranted, particularly in pediatric pts. The PK population consisted of 250 pts with advanced hematologic malignancies from 7 studies and included 46 (18%) pediatric pts (1-17 y) and 204 (82%) adults (≥18 y). The population included 148 (59%) males, mainly of white origin (82%). Nonlinear mixed-effect modeling was performed using NONMEM®. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and pertinent graphical representations of goodness-of-fit. Separate PK models were developed for cytarabine and daunorubicin; intrinsic and extrinsic factors were evaluated as covariates. The intrinsic factors included body weight, body mass index, age, sex, race, white blood cell count, and markers of renal function (creatinine clearance, serum creatinine) and hepatic function (bilirubin, aspartate and alanine aminotransferases, alkaline phosphatase). The extrinsic factors included study type (adult vs pediatric/young adult) and formulation (frozen vs lyophilized). Based on previous population PK models developed for adults, the PK models for cytarabine and daunorubicin used 2-compartment structural models, with drug input into the central compartment, first-order distribution between the central and peripheral compartments, and first-order elimination from the central compartment. Two-compartment structural models with body surface area (BSA) as an allometric scalar provided minimum bias in estimates of systemic clearance (CL) and volume of distribution for the central compartment (Vc). Based on the final population PK models, the estimates of CL and Vc in adults were 0.101 L/h and 4.76 L, respectively, for cytarabine and 0.140 L/h and 4.04 L for daunorubicin. The population estimates of CL and Vc for cytarabine in children, adolescents, and young adults (&amp;lt;22 y) were 0.073 L/h and 3.91 L, respectively, for cytarabine and 0.093 L/h and 3.28 L for daunorubicin. The population PK models included an allometric component that accounted for differences in BSA. The exponent for the effect of BSA on CL was 0.948 and 0.876 for cytarabine and daunorubicin, respectively, suggesting a faster clearance in pts with higher BSA. These differences in CL are expected to be offset by BSA-based dosing of CPX-351. Bilirubin and formulation (frozen) remained statistically significant covariates on the CL of daunorubicin. All tested covariates were eventually excluded from the population PK models, except BSA, bilirubin, study type, and formulation, which have a small effect on PK and are not expected to result in detectable changes in clinical safety or efficacy. Age was evaluated both as a continuous and categorical variable (1-5, 6-11, and 12-17 y) and was not a significant covariate for cytarabine and daunorubicin CL and Vc. Study type was identified as a significant covariate for CL and Vc for cytarabine and daunorubicin, which was possibly due to a change in analytical site for pediatric studies. Mean AUC0-48 values of cytarabine in pts aged 1-5, 6-11, and 12-17 y (135 U/m2) were similar (2767, 2783, and 2806 μg·h/mL, respectively) and approximately 40% higher than that observed in pts ≥18 y (100 U/m2, 1928 μg·h/mL), proportional to the 35% higher dose in pediatric pts. Mean AUC0-48 values of daunorubicin in pts aged 1-5, 6-11, and 12-17 y (135 U/m2) were similar (967, 896, and 982 μg·h/mL, respectively) and approximately 40% higher than that observed in pts ≥18 y (100 U/m2, 615 μg·h/mL), proportional to the 35% higher dose in pediatric pts. The results of this population PK analysis indicated exposures to CPX-351 in pediatric pts were not affected by age and were similar to those in adults when administered at the same BSA-normalized dose. Disclosures Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Absalon:Jazz Pharmaceuticals: Research Funding. OffLabel Disclosure: Yes, in this study, CPX-351 was also evaluated in pediatric AML

Efficacy of Artemether-Lumefantrine on various Plasmodium falciparum Kelch 13 and Pfmdr1 genes isolated in Ghana

IntroductionArtemether-Lumefantrine (A-L) remains the drug of choice for the treatment of uncomplicated malaria in Ghana. However, the pharmaco-activity of A-L has not been assessed on various Plasmodium falciparum Kelch 13 and Pfmdr1 genes. Therefore, this study sought to determine the therapeutic efficacy of A-L on P. falciparum parasites isolated from Ghana. MethodsThe clinical study was done in Ga West Municipality, Ghana, where 78 uncomplicated malaria patients were recruited with prior consent. The patients were treated orally with A-L according to national treatment guidelines. Baseline parasitaemia was determined before treatment and 8-hourly parasitaemia posttreatment were determined till initial clearance of parasitaemia and at days 7, 14, 21, and 28. Kelch 13 and Pfmdr1 genes were genotyped by sequencing using baseline samples. Parasite clearance characteristics were determined using Parasite Clearance Estimator beta 0.9 application. ResultsFive Kelch 13 (F446I, S466N, R539I, A578S, and A676S) and three Pfmdr1 mutations (N86Y, Y184F and D1246Y) were identified in 78 infected samples. About 8% of the samples contained two Pfmdr1 double mutations (N86Y & D1246Y and Y184F & N86Y). Additionally, three samples (3.8%) were found to contain both Kelch 13 mutations and Pfmdr1 wild type genes. In all patients, parasitaemia persisted within the first 24 h of A-L therapy. However, at hour 40, only two patients were parasitaemic while all patients were aparasitaemic at hour 48. The genotypic profiles of the two persistent parasites at hour 40 were F446I and D1246Y, and R539I, Y184F, and N86Y. The slope half-life of the former was 6.4 h while the latter was 6.9 h and their respective PCT99 were 47.9 h and 49.2 h as well as a clearance rate constants of 0.109 and 0.092 respectively. ConclusionThis study reports the effectiveness of A-L on various P. falciparum mutant alleles. However, continuous surveillance of Kelch 13 mutations and Pfmdr1 gene in Ghana and regular assessment of the therapeutic efficacy of A-L and other artemisinin derivatives is recommended.