The intact nephron hypothesis as a model for renal drug handling

Pradhan, Sudeep; Duffull, Stephen B.; Walker, Robert; Wright, Daniel F. B.

doi:10.1007/s00228-018-2572-8

Cited by 18 publications

(22 citation statements)

References 45 publications

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“…Subsequently, additional, biologically plausible, CKD virtual population models were investigated (Table I ). Three models based on mimicking the INH [ 21 , 22 ] assumed a decrease of either (i) proximal tubule cellularity, (ii) OAT1 abundance in proximal tubule cells, or (iii) OAT1 and multidrug and toxin extrusion (MATE) abundance in proximal tubule cells, in proportion to the disease-related decrease in GFR. Another assumption explored was that proximal tubule cellularity declines proportionally to GFR, while changes in OAT1 activity were disproportionate to these changes which would account for the effect of uremic solutes on OAT1 (Table I ).…”

Section: Methodsmentioning

confidence: 99%

“…in line with the 'intact nephron hypothesis' (INH, [21]) or non-proportional to corresponding changes in glomerular filtration rate. The consistency of these various plausible mechanisms (and their extent) in explaining clinical PK data in CKD patients has been explored using both empirical and mechanistic/PBPK models [14,20,[22][23][24][25][26]. In addition to plasma concentrations, the structural complexity of mechanistic kidney models enables simulation of local (intra-tubular) drug exposure and regional tubular differences and assessment of certain scenarios (e.g.…”

Section: Introductionmentioning

confidence: 99%

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PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake

Scotcher

Galetin

2021

AAPS J

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Dosing guidance is often lacking for chronic kidney disease (CKD) due to exclusion of such patients from pivotal clinical trials. Physiologically based pharmacokinetic (PBPK) modelling supports model-informed dosing when clinical data are lacking, but application of these approaches to patients with impaired renal function is not yet at full maturity. In the current study, a ganciclovir PBPK model was developed for patients with normal renal function and extended to CKD population. CKD-related changes in tubular secretion were explored in the mechanistic kidney model and implemented either as proportional or non-proportional decline relative to GFR. Crystalluria risk was evaluated in different clinical settings (old age, severe CKD and low fluid intake) by simulating ganciclovir medullary collecting duct (MCD) concentrations. The ganciclovir PBPK model captured observed changes in systemic pharmacokinetic endpoints in mild-to-severe CKD; these trends were evident irrespective of assumed pathophysiological mechanism of altered active tubular secretion in the model. Minimal difference in simulated ganciclovir MCD concentrations was noted between young adult and geriatric populations with normal renal function and urine flow (1 mL/min), with lower concentrations predicted for severe CKD patients. High crystalluria risk was identified at reduced urine flow (0.1 mL/min) as simulated ganciclovir MCD concentrations exceeded its solubility (2.6–6 mg/mL), irrespective of underlying renal function. The analysis highlighted the importance of appropriate distribution of virtual subjects’ systems data in CKD populations. The ganciclovir PBPK model illustrates the ability of this translational tool to explore individual and combined effects of age, urine flow, and renal impairment on local drug renal exposure. Graphical Abstract

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake

Scotcher

Galetin

2021

AAPS J

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“…Kidney disease and acute kidney injury in dogs is detected using serum creatinine concentration, among other criteria. Although increases in serum creatinine concentration are associated with low glomerular filtration rate (GFR) in dogs, 10 it is an imperfect clinical surrogate to predict drug clearance, and decreased GFR might not predict clearance for drugs that undergo tubular secretion 11,12 . However, serum creatinine concentration is the most often surrogate measure used to stage kidney disease in dogs.…”

Section: Introductionmentioning

confidence: 99%

Ampicillin pharmacokinetics in azotemic and healthy dogs

Monaghan

Labato

Papich

2021

Veterinary Internal Medicne

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Background: Little is known about effects of factors such as kidney disease, affecting ampicillin pharmacokinetics in dogs. Objectives: Determine the pharmacokinetics of ampicillin after a single intravenous dose in healthy and azotemic dogs. Animals: Nine dogs presenting with acute kidney injury and 10 healthy dogs. Methods: This was a prospective study. An ampicillin dose of 22.2 mg/kg (mean dose) was administered once intravenously. Blood samples were obtained at timed intervals (just before administration, 1, 2, 4, 12, and 24 hours), analyzed using highpressure liquid chromatography followed by pharmacokinetic analysis of the plasma drug concentrations. Results: Peak ampicillin concentration (mcg/mL; 97.07 (36.1) vs 21.3 (50.26)), P<.001 (geometric mean (coefficient of variation, CV%)), half-life (hours; 5.86 (56.55) vs 0.97 (115.3)), P<.001) and AUC (h × mcg/mL; 731.04 (83.75) vs 33.57 (53.68)), P<.001) were greater in azotemic dogs than in healthy dogs. Azotemic dogs also had significantly lower clearance (30.06 (84.19) vs 655.03 (53.67); mL/kg h, P < .001) and volume of distribution (253.95 (30.14) vs 916.93 (135.24); mL/kg, P <.001) compared to healthy dogs. Conclusion and Clinical Importance: Increased drug concentrations and slower clearance of ampicillin in azotemic dogs could have clinical importance in contributing to antibiotic associated morbidity requiring indicating the need to adjust ampicillin dosing in dogs with decreased kidney function.

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“…Morphine clearance in children was similar to the mature value described by others for adults and children. 21,44,45 Similarly clearance of metabolites correlated with glomerular filtration rate, a measure of renal function 46 that matures over the first year of life 47 .…”

Section: Discussionmentioning

confidence: 99%

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

Gastine

Morse

Leung

et al. 2022

BMJ Support Palliat Care

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BackgroundIntranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation.AimTo determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics.DesignA systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed.Review sourcesPubMed (1960–2020); EMBASE (1980–2020); IPA (1973–2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration.ResultsThe systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4–88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites.ConclusionsWe estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4–13 years.

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The intact nephron hypothesis as a model for renal drug handling

Cited by 18 publications

References 45 publications

PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake

PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake

Ampicillin pharmacokinetics in azotemic and healthy dogs

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

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