In Vitro to In Vivo Scalars for Drug Clearance in Nonalcoholic Fatty Liver and Steatohepatitis.

In vitro-in vivo extrapolation (IVIVE) allows prediction of clinical outcomes across populations from in vitro data using specific scalars tailored to the biologic characteristics of each population. This study experimentally determined scalars for patients with varying degrees of nonalcoholic fatty liver disease (NAFLD), ranging from fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. Microsomal, S9, and cytosol fractions were extracted from 36 histologically normal and 66 NAFLD livers (27 nonalcoholic fatty liver [NAFL], 13 NASH, and 26 NASH with cirrhosis). Corrected microsomal protein per gram liver (MPPGL) progressively decreased with disease severity (26.8, 27.4, and 24.3 mg/g in NAFL, NASH, and NASH/cirrhosis, respectively, compared with 35.6 mg/g in normal livers; ANOVA, P < 0.001). Homogenate, S9, and cytosolic protein showed a consistent trend of decline in NASH/cirrhosis relative to normal control (post-hoc t test, P < 0.05). No differences across the groups were observed in homogenate, S9, cytosolic, and microsomal protein content in matched kidney samples. MPPGL-based scalars that combine protein content with liver size revealed that the reduction in MPPGL in NAFL and NASH was compensated by the reported increase in liver size (relative scalar ratios of 0.96 and 0.99, respectively), which was not the case with NASH/cirrhosis (ratio of 0.63), compared with healthy control. Physiologically based pharmacokinetics-informed global sensitivity analysis of the relative contribution of IVIVE scalars (hepatic CYP3A4 abundance, MPPGL, and liver size) to variability in exposure (area under the curve) to three CYP3A substrates (alprazolam, midazolam, and ibrutinib) revealed enzyme abundance as the most significant parameter, followed by MPPGL, whereas liver volume was the least impactful factor. SIGNIFICANCE STATEMENT: Nonalcoholic fatty liver disease-specific scalars necessary for extrapolation from in vitro systems to liver tissue are lacking. These are required in clearance prediction and dose selection in nonalcoholic fatty liver and steatohepatitis populations. Previously reported disease-driven changes have focused on cirrhosis, with no data on the initial stages of liver disease. The authors obtained experimental values for microsomal, cytosolic, and S9 fractions and assessed the relative impact of microsomal scalars on predicted exposure to substrate drugs using physiologically based pharmacokinetics.

Antibody Drug Clearance: An Underexplored Marker of Outcomes with Checkpoint Inhibitors.

Immune-checkpoint inhibitor (ICI) therapy has dramatically changed the clinical landscape for several cancers, and ICI use continues to expand across many cancer types. Low baseline clearance (CL) and/or a large reduction of CL during treatment correlates with better clinical response and longer survival. Similar phenomena have also been reported with other monoclonal antibodies (mAb) in cancer and other diseases, highlighting a characteristic of mAb clinical pharmacology that is potentially shared among various mAbs and diseases. Though tempting to attribute poor outcomes to low drug exposure and arguably low target engagement due to high CL, such speculation is not supported by the relatively flat exposure-response relationship of most ICIs, where a higher dose or exposure is not likely to provide additional benefit. Instead, an elevated and/or increasing CL could be a surrogate marker of the inherent resistant phenotype that cannot be reversed by maximizing drug exposure. The mechanisms connecting ICI clearance, therapeutic efficacy, and resistance are unclear and likely to be multifactorial. Therefore, to explore the potential of ICI CL as an early marker for efficacy, this review highlights the similarities and differences of CL characteristics and CL-response relationships for all FDA-approved ICIs, and we compare and contrast these to selected non-ICI mAbs. We also discuss underlying mechanisms that potentially link mAb CL with efficacy and highlight existing knowledge gaps and future directions where more clinical and preclinical investigations are warranted to clearly understand the value of baseline and/or time-varying CL in predicting response to ICI-based therapeutics.

Meropenem Clearance in a Child With End-stage Renal Disease Undergoing Prolonged Intermittent Renal Replacement Therapy: A Case Report and Literature Review.

BACKGROUND: Meropenem is frequently used to treat severe infections in critically ill children. However, pharmacokinetic data on meropenem in children with end-stage renal disease (ESRD) undergoing prolonged intermittent renal replacement therapy (PIRRT) is limited. Our objectives were to evaluate meropenem clearance in a child with ESRD with and without PIRRT, compare the results to previous continuous renal replacement therapy studies in children, toddlers and neonates, and assess whether the currently used dose of meropenem is sufficient. CASE DESCRIPTION: A 5-year-old girl with an estimated glomerular filtration rate of 12.8 mL/min/1.73 m 2 was diagnosed with pulmonary infection and treated with 300 mg meropenem once a day. PIRRT was performed for 8 hours every 2 days. We used WinNonlin to evaluate meropenem clearance with and without PIRRT. RESULTS: Our case showed that PIRRT increased the clearance of meropenem from 1.39 (1.3) to 2.42 L/h (2.3 mL/kg/min) and caught up 42.6% of the total clearance. This result is in accordance with previous studies in children but slightly less than seen in toddlers and neonates under continuous renal replacement therapy. The current dose of 300 mg once a day is not sufficient to reach the therapeutic target. CONCLUSIONS: Predicting meropenem clearance in children with ESRD undergoing PIRRT is difficult as clearance will be affected by renal function, PIRRT settings and other factors. Further studies are needed to explore the individual variability of meropenem clearance and optimize the dosing regimen.

Induction of open-form bile canaliculus formation by hepatocytes for evaluation of biliary drug excretion.

Biliary excretion is a major drug elimination pathway that affects their efficacy and safety. The currently available in vitro sandwich-cultured hepatocyte method is cumbersome because drugs accumulate in the closed bile canalicular lumen formed between hepatocytes and their amounts cannot be mealsured directly. This study proposes a hepatocyte culture model for the rapid evaluation of drug biliary excretion using permeation assays. When hepatocytes are cultured on a permeable support coated with the cell adhesion protein claudins, an open-form bile canalicular lumen is formed at the surface of the permeable support. Upon application to the basolateral (blood) side, drugs appear on the bile canalicular side. The biliary excretion clearance of several drugs, as estimated from the obtained permeabilities, correlates well with the reported in vivo biliary excretion clearance in humans. Thus, the established model is useful for applications in the efficient evaluation of biliary excretion during drug discovery and development.

Estimates of Drug Metabolism Using Drug Excretion Concentrations.

We propose that quantitative urine drug concentrations from LC-MS/MS measurements can be used to estimate zero and first order pharmacokinetics of the drugs oxycodone, hydrocodone, buprenorphine, methadone, and fentanyl. We observed the ratio of metabolite to parent drug could be used for this estimate. As the amount of observed parent drug increased, the metabolic ratio decreased, indicating a shift from first order to zero order metabolism. After making assumptions of bioavailability, percent of drug excreted into urine, we developed estimates of the saturating dosages for these drugs.

Long-Term Intake of Linezolid Elevates Drug Exposure and Reduces Drug Clearance and Elimination in Adults With Drug-Resistant Pulmonary Tuberculosis.

PURPOSE: Pharmacokinetic (PK) studies are critical for dose optimization, and there is a paucity of linezolid (LZD) PK data for prolonged use in drug-resistant tuberculosis (DR-TB). Therefore, the authors evaluated the pharmacokinetics of LZD at two-time intervals in DR-TB during long-term use. METHODS: PK evaluation of LZD was performed at the end of the 8th and 16th weeks of treatment in a randomly selected subset of adult pre-extensively drug-resistant pulmonary tuberculosis patients (n = 18) from a multicentric interventional study (Building Evidence to Advance Treatment of TB/BEAT study; CTRI/2019/01/017310), wherein a daily dose of 600 mg LZD was used for 24 weeks. Plasma LZD levels were measured using a validated high-pressure liquid chromatography (HPLC) method. RESULTS: The LZD median plasma C max was comparable between the 8th and 16th weeks [18.3 mg/L, interquartile range (IQR: 15.5-20.8 and 18.8 mg/L, IQR: 16.0-22.7, respectively)]. However, the trough concentration increased significantly in the 16th week (3.16 mg/L, IQR: 2.30-4.76), compared with the 8th week (1.98 mg/L, IQR: 0.93-2.75). Furthermore, compared with the 8th week, in the 16th week, there was a significant increase in drug exposure (AUC 0-24 = 184.2 mg*h/L, IQR: 156.4-215.8 versus 233.2 mg*h/L, IQR: 187.9-277.2), which corroborated with a longer elimination half-life (6.94 hours, IQR: 5.55-7.99 versus 8.47 hours, IQR:7.36-11.35) and decreased clearance (2.91 L/h, IQR: 2.45-3.33 versus 2.19 L/h, IQR: 1.49-2.78). CONCLUSIONS: Long-term daily intake of 600 mg LZD resulted in a significant elevation in trough concentration (>2.0 mg/L) in 83% of the study participants. Furthermore, increased LZD drug exposure may be partly because of decreased clearance and elimination. Overall, the PK data underscore the need for dose adjustment when LZDs are intended for long-term treatment.

Narrative review of migraine management in patients with renal or hepatic disease.

OBJECTIVES/BACKGROUND: Treatment of migraine in the setting of either renal or hepatic disease can be daunting for clinicians. Not only does the method of metabolism have to be considered, but also the method of elimination/excretion of the parent drug and any active or toxic metabolites. Furthermore, it is difficult to think about liver or kidney disease in isolation, as liver disease can sometimes contribute to impaired renal function and renal disease can sometimes impair hepatic metabolism, through the cytochrome P450 system. METHODS: A detailed search for terms related to liver disease, renal disease, and migraine management was performed in PubMed, Ovid Medline, Embase, and the Cochrane Library.For each medication, product labels were retrieved and reviewed using the US FDA website, with additional review of IBM Micromedex, LiverTox, and the Renal Drug Handbook. RESULTS: This manuscript provides an overview of migraine drug metabolism and how it can be affected by liver and renal impairment. It reviews the standard terminology recommended by the US Food and Drug Administration for the different stages of hepatic and renal failure. The available evidence regarding the use of abortive and preventative medicines in the setting of organ failure is discussed in detail, including more recent therapies such as lasmiditan, gepants, and calcitonin gene-related peptide antibodies. CONCLUSIONS: For acute therapy, the use of NSAIDS should be limited, as these carry risk for both severe hepatic and renal disease. Triptans can be selectively used, often with dose guideline adjustments. Ubrogepant may be used in severe hepatic disease with dose adjustment and lasmiditan can be used in end stage renal disease. Though non-medicine strategies may be the most reasonable initial approach, many preventative medications can be used in the setting of hepatic and renal disease, often with dose adjustment. This review provides tables of guidelines, including reduced dosing recommendations, for the use of abortive and preventative migraine medications in hepatic and renal failure.

Amplifying the impact of kidney microphysiological systems: predicting renal drug clearance using mechanistic modelling based on reconstructed drug secretion.

Accurate prediction of pharmacokinetic parameters, such as renal clearance, is fundamental to the development of effective and safe new treatments for patients. However, conventional renal models have a limited ability to predict renal drug secretion, a process that is dependent on transporters in the proximal tubule. Improvements in microphysiological systems (MPS) have extended our in vitro capabilities to predict pharmacokinetic parameters. In this study a kidney-MPS model was developed that successfully recreated renal drug secretion. Human proximal tubule cells grown in the kidney-MPS, resem­bling an in vivo phenotype, actively secreted the organic cation drug metformin and organic anion drug cidofovir, in contrast to cells cultured in conventional culture formats. Metformin and cidofovir renal secretory clearance were predicted from kid­ney-MPS data within 3.3- and 1.3-fold, respectively, of clinically reported values by employing a semi-mechanistic drug distribution model using kidney-MPS drug transport parameters together with in vitro to in vivo extrapolation. This approach introduces an effective application of a kidney-MPS model coupled with pharmacokinetic modelling tools to evaluate and predict renal drug clearance in humans. Kidney-MPS renal clearance predictions can potentially complement pharma-cokinetic animal studies and contribute to the reduction of pre-clinical species use during drug development.

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life.

Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CLH ) and renal clearance (CLR ). The typical value of the total clearance (CL, the sum of CLR and CLH ) was 3.09 ml/h and expressed as CL/WTmedian  = 3.96 ml/h/kg, where WTmedian is the median body weight. The intersubject variability of CLR and CLH were 61% and 207%, respectively. The typical value of the volume of distribution Vp  = 366 ml (Vp /WTmedian  = 470 ml/kg), and its intersubject variability was 38.8%. Half-life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model-informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change.

Drug clearance by aldehyde oxidase: can we avoid clinical failure?

Despite increased awareness of aldehyde oxidase (AO) as a major drug-metabolising enzyme, predicting the pharmacokinetics of its substrates remains challenging. Several drug candidates have been terminated due to high clearance, which were subsequently discovered to be AO substrates. Even retrospective extrapolation of human clearance, from models more sensitive to AO activity, often resulted in underprediction.The questions of the current work thus were: Is there an acceptable degree of in vitro AO metabolism that does not result in high in vivo human clearance? And, if so, how can this be predicted?We built an in vitro/in vivo correlation using known AO substrates, combining multiple in vitro parameters to calculate the blood metabolic clearance mediated by AO (CLbAO). This value was compared with observed blood clearance (CLb-obs), establishing cut-off CLbAO values, to discriminate between low and high CLb-obs. The model was validated using additional literature compounds, and CLb-obs was predicted in the correct category.This simple, categorical, semi-quantitative yet multi-factorial model is readily applicable in drug discovery. Further, it is valuable for high-clearance compounds, as it predicts the CLb group, rather than an exact CLb value, for the substrates of this poorly-characterised enzyme.

Comparison of different equations for renal function evaluation as proxies for antibiotic drug clearance: The examples of amoxicillin and cloxacillin.

The most appropriate renal function estimation equation to predict drug clearance is a matter of debate. In this study, we compare the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) and the Cockroft-Gault (CG) equations to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving high doses of these antibiotic treatments. This study aimed to compare different equations used to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving amoxicillin or cloxacillin treatments outside the intensive care unit. Data from 128 patients contributing 268 plasma samples was analyzed, and correlations between the equations and the amoxicillin and cloxacillin antibiotic clearance rates were calculated. We found a correlation between antibiotic clearance and all the renal function estimation equations, CG being the best, with a R2 of 0.35 for amoxicillin and 0.29 for cloxacillin (compared to 0.26 and 0.21 for MDRD and 0.12 and 0.24 for CKD-EPI). CG should be preferentially used as a proxy for amoxicillin and cloxacillin drug clearance, but the use of completely different tools such as therapeutic drug monitoring could help individualize antibiotic dosage.

Predicting Total Drug Clearance and Volumes of Distribution Using the Machine Learning-Mediated Multimodal Method through the Imputation of Various Nonclinical Data.

Pharmacokinetic research plays an important role in the development of new drugs. Accurate predictions of human pharmacokinetic parameters are essential for the success of clinical trials. Clearance (CL) and volume of distribution (Vd) are important factors for evaluating pharmacokinetic properties, and many previous studies have attempted to use computational methods to extrapolate these values from nonclinical laboratory animal models to human subjects. However, it is difficult to obtain sufficient, comprehensive experimental data from these animal models, and many studies are missing critical values. This means that studies using nonclinical data as explanatory variables can only apply a small number of compounds to their model training. In this study, we perform missing-value imputation and feature selection on nonclinical data to increase the number of training compounds and nonclinical datasets available for these kinds of studies. We could obtain novel models for total body clearance (CLtot) and steady-state Vd (Vdss) (CLtot: geometric mean fold error [GMFE], 1.92; percentage within 2-fold error, 66.5%; Vdss: GMFE, 1.64; percentage within 2-fold error, 71.1%). These accuracies were comparable to the conventional animal scale-up models. Then, this method differs from animal scale-up methods because it does not require animal experiments, which continue to become more strictly regulated as time passes.

Development and Use of an Ex-Vivo In-Vivo Correlation to Predict Antiepileptic Drug Clearance in Patients Undergoing Continuous Renal Replacement Therapy.

OBJECTIVES: Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations. METHODS: Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2 g/dL, 3 g/dL, and 4 g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr). Blood and effluent/dialysate concentrations were collected after circuit priming. ECs were calculated for each drug, modality, vehicle, and experimental arm combination. RESULTS: The calculated average EC for levetiracetam and lacosamide was approximated to the fraction unbound from plasma protein. Human plasma and ALB-NS vehicles demonstrated adequate prediction of in-vivo CRRT clearance. Geometric mean ratios indicated similarity in extraction coefficients when comparing between hemofiltration and hemodiafiltration modalities and between filtration and dialysis modalities at effluent flow rates ≤ 2L/hr. Evaluation of phenytoin provided inconsistent findings with regards to extraction coefficient similarity across different CRRT modalities. CONCLUSION: The findings indicate that an ex-vivo study can be used as a surrogate to predict in-vivo levetiracetam and lacosamide clearance in patients receiving CRRT.

A General Biphasic Bodyweight Model for Scaling Basal Metabolic Rate, Glomerular Filtration Rate, and Drug Clearance from Birth to Adulthood.

The objective of this study is to propose a unified, continuous, and bodyweight-only equation to quantify the changes of human basal metabolic rate (BMR), glomerular filtration rate (GFR), and drug clearance (CL) from infancy to adulthood. The BMR datasets were retrieved from a comprehensive historical database of male and female subjects (0.02 to 64 years). The CL datasets for 17 drugs and the GFR dataset were generated from published maturation and growth models with reported parameter values. A statistical approach was used to simulate the model-generated CL and GFR data for a hypothetical population with 26 age groups (from 0 to 20 years). A biphasic equation with two power-law functions of bodyweight was proposed and evaluated as a general model using nonlinear regression and dimensionless analysis. All datasets universally reveal biphasic curves with two distinct linear segments on log-log plots. The biphasic equation consists of two reciprocal allometric terms that asymptotically determine the overall curvature. The fitting results show a superlinear scaling phase (asymptotic exponent >1; ca. 1.5-3.5) and a sublinear scaling phase (asymptotic exponent <1; ca. 0.5-0.7), which are separated at the phase transition bodyweight ranging from 5 to 20 kg with a mean value of 10 kg (corresponding to 1 year of age). The dimensionless analysis generalizes and offers quantitative realization of the maturation and growth process. In conclusion, the proposed mixed-allometry equation is a generic model that quantitatively describes the phase transition in the human maturation process of diverse human functions.

A Semi-Physiological Three-Compartment Model Describes Brain Uptake Clearance and Efflux of Sucrose and Mannitol after IV Injection in Awake Mice.

PURPOSE: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake. METHODS: Stable isotope-labeled [13C]sucrose and [13C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (Kin) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance. RESULTS: The three-compartment model was able to describe the experimental data well, yielding estimates for Kin of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 µl.min-1.g-1, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) µl.min-1.g-1, which were not statistically different. Kin values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points. CONCLUSIONS: Using the three-compartment model allows determination of Kin for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.

Model-Based Assessment of the Contribution of Monocytes and Macrophages to the Pharmacokinetics of Monoclonal Antibodies.

PURPOSE: We have hypothesized that a high concentration of circulating monocytes and macrophages may contribute to the fast weight-based clearance of monoclonal antibodies (mAbs) in young children. Exploring this hypothesis, this work uses modeling to clarify the role of monocytes and macrophages in the elimination of mAbs. METHODS: Leveraging pre-clinical data from mice, a minimal physiologically-based pharmacokinetic model was developed to characterize mAb uptake and FcRn-mediated recycling in circulating monocytes, macrophages, and endothelial cells. The model characterized IgG disposition in complex scenarios of site-specific FcRn deletion and variable endogenous IgG levels. Evaluation was performed for predicting IgG disposition with co-administration of high dose IVIG. A one-at-a-time sensitivity analysis quantified the role of relevant cellular parameters on IgG elimination in various scenarios. RESULTS: The plasma AUC of mAbs was highly sensitive to endothelial cell parameters, but had near-nil sensitivity to monocyte and macrophage parameters, even in scenarios with 90% loss of FcRn expression/activity. In mice with normal FcRn expression, simulations suggest that less than 2% of an IV dose is eliminated in macrophages, while endothelial cells are predicted to dominate mAb elimination. CONCLUSIONS: The model suggests that the role of monocytes and macrophages in IgG homeostasis includes extensive uptake and highly efficient FcRn-mediated protection, but not appreciable degradation when FcRn is present. Therefore, it is very unlikely that a high concentration of circulating monocytes can contribute to explaining the fast weight-based clearance of mAbs in very young children, even if FcRn expression/activity was 90% lower in children than in adults.

Predicting the Drug Clearance Pathway with Structural Descriptors.

BACKGROUND AND OBJECTIVE: The clearance, by renal elimination or hepatic metabolism, is one of the most important pharmacokinetic parameters of a drug. It allows the half-life, bioavailability, and drug-drug interactions to be predicted, and it can also affect the dose regimen of a drug. Predicting the clearance pathways of new chemical candidates during drug development is vital in order to minimize the risks of possible side effects and drug interactions. Many in vivo methods have been established to predict drug clearance in humans, and these mainly rely on data from in vivo studies in preclinical species-mainly rats, dogs, and monkeys. They are also time consuming and expensive. The aim of this study was to find the relationship between structural parameters of drugs and their clearance pathways. METHODS: The clearance pathway of each drug was obtained from the literature. Various structural descriptors [Abraham solvation parameters, topological polar surface area, numbers of hydrogen-bond donors and acceptors, number of rotatable bonds, molecular weight, logarithm of the partition coefficient (logP), and logarithm of the distribution coefficient at pH 7.4 (logD7.4)] were applied to develop a mechanistic model for predicting clearance pathways. RESULTS: The results of this study indicate that compounds with logD7.4 > 1 or with zero or one hydrogen-bond donor undergo hepatic metabolism, whereas the clearance pathway for chemicals with logD7.4 < - 2 is renal elimination. Furthermore, models established using logistic regression based on five structural parameters for compounds with - 2 < logD7.4 < 1 could be used in a clearance pathway prediction tool. The overall prediction accuracies of the first and second models were 84.8% and 84.4%, respectively. CONCLUSION: The developed model can be used to find the clearance pathways of new drug candidates with acceptable accuracy. The main descriptors that are used to evaluate this parameter are the hydrophobicity and the number of hydrogen-bonding functional groups of the compound.

An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables.

INTRODUCTION: When pediatric data are not available for a drug, allometric and other methods are applied to scale drug clearance across the pediatric age-range from adult values. This is applied when designing first-in-child studies, but also for off-label drug prescription. AREAS COVERED: This review provides an overview of the systematic accuracy of allometric and other pediatric clearance scaling methods compared to gold-standard PBPK predictions. The findings are summarized in decision tables to provide a priori guidance on the selection of appropriate pediatric clearance scaling methods for both novel drugs for which no pediatric data are available and existing drugs in clinical practice. EXPERT OPINION: While allometric scaling principles are commonly used to scale pediatric clearance, there is no universal allometric exponent (i.e. 1, 0.75, or 0.67) that can accurately scale clearance for all drugs from adults to children of all ages. Therefore, pediatric scaling decision tables based on age, drug elimination route, binding plasma protein, fraction unbound, extraction ratio, and/or isoenzyme maturation are proposed to a priori select the appropriate (allometric) clearance scaling method, thereby reducing the need for full PBPK-based clearance predictions. Guidance on allometric scaling when estimating pediatric clearance values is provided as well.

Alemtuzumab clearance, lymphocyte count, and T-cell chimerism after hematopoietic stem cell transplant in sickle cell disease.

STUDY OBJECTIVE: Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes. DESIGN: PK and PD analysis of patient data from a single-center clinical trial. SETTING: Clinical research center. PATIENTS: Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI). MEASUREMENTS AND MAIN RESULTS: Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R2  = 0.40 and p = 0.004 at 2 months, R2  = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism. CONCLUSION: Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.