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

AbstractDosing 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

Download Full-text

Single-Dose Study to Evaluate the PKs of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function

Case Medical Research ◽

10.31525/ct1-nct03896750 ◽

2019 ◽

Author(s):

Keyword(s):

Renal Function ◽

Single Dose ◽

Renal Impairment ◽

Normal Renal Function ◽

Single Dose Study ◽

Dose Study

Download Full-text

SINGLE-DOSE PHARMACOKINETICS OF BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) IN PARTICIPANTS WITH NORMAL RENAL FUNCTION AND PARTICIPANTS WITH MODERATE OR SEVERE RENAL IMPAIRMENT

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(21)03195-8 ◽

2021 ◽

Vol 77 (18) ◽

pp. 1839

Author(s):

Vidya Perera ◽

Grigor Abelian ◽

Danshi Li ◽

Zhaoqing Wang ◽

Liping Zhang ◽

...

Keyword(s):

Renal Function ◽

Single Dose ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment

Download Full-text

P0234LOW URINARY CITRATE LEVELS ARE NOT SPECIFIC OF AUTOSOMAL POLYCYSTIC KIDNEY DISEASE (ADPKD) AND ARE PRESENT WHEN RENAL FUNCTION IS IMPAIRED IN ALL NEPHROPATIES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0234 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Francisco-Jose Borrego-Utiel ◽

Enoc Merino Garcia ◽

Isidoro Herrera ◽

Clara Moriana Dominguez ◽

Victoria Camacho Reina ◽

...

Keyword(s):

Renal Function ◽

Uric Acid ◽

Kidney Disease ◽

Renal Impairment ◽

Polycystic Kidney Disease ◽

Normal Renal Function ◽

Serum Bicarbonate ◽

Polycystic Kidney ◽

Glomerular Diseases ◽

Urinary Citrate

Abstract Background and Aims In polycystic kidney disease (PKD) it is frequently found a reduction in urinary citrate that is related with degree of renal impairment but it is unknown if this alteration is specific or if it is also present in other nephropathies. Recently it has been suggested that urinary citrate could be a marker of covert metabolic acidosis and reflects acid retention in chronic kidney disease (CKD). Our aim was to compare urinary citrate in PKD with other renal diseases and to show its relation with serum bicarbonate and excretion of uric acid and calcium. Method We determined citrate, calcium and uric acid in 24-hour urine in patients with PKD and with other nephropathies with varied degree of renal impairment followed in a outpatient clinic of nephrology. Results We included 291 patients, 119 with glomerular diseases, 116 with PKD, 21 with other nephropathies, and 35 patients with normal renal function. Urinary citrate was higher in women (Females 309±251 mg/gCr vs. males 181±145 mg/gCr, p<0.001) and in patients with normal renal function (normal 380±210 mg/gCr; PKD 203±166 mg/gCr; glomerular 279±282 mg/gCr; p<0,001). PKD patients showed similar values of urinary citrate to patients with glomerular diseases and with other nephropathies. We observed a progressive reduction in urinary citrate parallel to degree of renal impairment, in a comparable way among patients with PKD and glomerular diseases. We did not observe a relationship between urinary citrate and serum bicarbonate levels. Calcium and uric acid elimination in ADPKD patients was similar to other nephropathies and lower to patients with normal renal function. However, serum uric acid was significantly higher in glomerular patients than other nephropathies after adjust with glomerular filtration rate and sex. Conclusion Hypocitraturia is not specific of PKD but it is also present in all nephropathies. Urinary citrate are related to degree of renal impairment and it is not related with serum bicarbonate. We think that it could be interesting to study urinary citrate as a marker of renal function and its role as prognostic factor of renal deterioration.

Download Full-text

Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1514 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1514-1519 ◽

Cited By ~ 64

Author(s):

A E Heald ◽

P H Hsyu ◽

G J Yuen ◽

P Robinson ◽

P Mydlow ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Renal Function ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment ◽

Moderate Renal Impairment ◽

Pharmacokinetic Parameters ◽

Geometric Means ◽

Immunodeficiency Virus

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.

Download Full-text

An audit of lithium prescribing practices in an old age psychiatry service highlighting renal impairment in this cohort

BJPsych Open ◽

10.1192/bjo.2021.323 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S109-S110

Author(s):

Leia Valentine ◽

John Cannon ◽

Siobhan Marmion ◽

Michelle Corcoran ◽

Marguerite Cryan ◽

...

Keyword(s):

Older Adults ◽

Renal Function ◽

Renal Impairment ◽

Old Age ◽

Thyroid Function ◽

Serum Calcium ◽

Prescribing Practices ◽

Lithium Level ◽

Increased Risk ◽

One Year

AimsTo compare Lithium prescribing practices in a Psychiatry of Old Age (POA) Service in the North-West of Ireland among adults aged 65 years and over with best practice guidelines.MethodReview of the literature informed development of audit standards for Lithium prescribing. These included National Institute for Clinical Excellent (NICE) 2014 guidelines, The British National Formulary (2019) and Maudsley Prescribing Guidelines (2018). Data were collected retrospectively, using an audit-specific data collection tool, from clinical files of POA team caseload, aged 65 years or more and prescribed Lithium over the past one year.ResultAt the time of the audit in February 2020, 18 patients were prescribed lithium, 67% female, average age 74.6 years. Of those prescribed Lithium; 50% (n = 9) had a depression diagnosis, 44% (n = 8) had bipolar affective disorder (BPAD) and 6% (n = 1) had schizoaffective disorder.78% (n = 14) of patients were on track to meet, or had already met, the NICE standard of 3-monthly serum lithium level. Lithium levels were checked on average 4.5 times in past one year, average lithium level was 0.61mmol/L across the group and 39% (n = 7) had lithium level within recommended therapeutic range (0.6-0.8mmol/L).83% (n = 15) of patients met the NICE standards of 3 monthly renal tests, thyroid function test was performed in 89% (n = 16) and at least one serum calcium level was documented in 63% (n = 15). Taking into consideration most recent blood test results, 100% (n = 18) had abnormal renal function, 78% (n = 7) had abnormal thyroid function and 60% (n = 9) had abnormal serum calcium.Half (n = 9) were initiated on lithium by POA service and of these, 56% (n = 5) had documented renal impairment prior to initiation. Of patients on long term lithium therapy at time of referral (n = 9), almost half (n = 4) had a documented history of lithium toxicity.ConclusionThe results of this audit highlight room for improvement in lithium monitoring of older adults attending POA service. Furthermore, all patients prescribed lithium had impaired renal function, half had abnormal calcium and two fifths had abnormal thyroid function. This is an important finding given the associations between those admitted to hospital with COVID-19 and comorbid kidney disease and increased risk of inpatient death.Our findings highlight the need for three monthly renal function monitoring in older adults prescribed lithium given the additive adverse effects of increasing age and lithium on the kidney. Close working with specialised renal services to provide timely advice on renal management for those with renal impairment prescribed lithium is important to minimise adverse patient outcomes.

Download Full-text