The Development of a PBPK Model for Atomoxetine Using Levels in Plasma, Saliva and Brain Extracellular Fluid in Patients with Normal and Deteriorated Kidney Function

2021 ◽  
Vol 20 ◽  
Author(s):  
Mo'tasem Mohamed Alsmadi ◽  
Laith Naser AL-Eitan ◽  
Nasir Mohammed Idkaidek ◽  
Karem Hasan Alzoubi
Keyword(s):  
Renal Impairment ◽  
Pbpk Model ◽  
Extracellular Fluid ◽  
Cyp2d6 Activity ◽  
Brain Extracellular Fluid ◽  
Hyperactivity Disorder ◽  
Physiologically Based Pharmacokinetic ◽  
Chemically Induced ◽  
Stage Renal Disease ◽  
End Stage

Background: Atomoxetine is a treatment for attention-deficit hyperactivity disorder. It inhibits norepinephrine transporters (NET) in the brain. Renal impairment can reduce hepatic CYP2D6 activity and atomoxetine elimination which may increase its body exposure. Atomoxetine can be secreted in saliva. Objective: The objective of this work was to test the hypothesis that atomoxetine saliva levels (sATX) can be used to predict ATX brain extracellular fluid (bECF) levels and their pharmacological effects in healthy subjects and those with end-stage renal disease (ESRD). Methods: The pharmacokinetics of atomoxetine after intravenous administration to rats with chemically induced acute and chronic renal impairments were investigated. A physiologically-based pharmacokinetic (PBPK) model was built and verified in rats using previously published measured atomoxetine levels in plasma and brain tissue. The rat PBPK model was then scaled to humans and verified using published measured atomoxetine levels in plasma, saliva, and bECF. Results: The rat PBPK model predicted the observed reduced atomoxetine clearance due to renal impairment in rats. The PBPK model predicted atomoxetine exposure in human plasma, sATX, and bECF. Additionally, it predicted that ATX bECF levels needed to inhibit NET are achieved at 80 mg dose. In ESRD patients, the developed PBPK model predicted that the previously reported 65% increase in plasma exposure in these patients could be associated with a 63% increase in bECF. The PBPK simulations showed that there is a significant correlation between sATX and bECF in humans. Conclusion: Saliva levels can be used to predict atomoxetine pharmacological response.

scholarly journals Lithium and Renal Impairment: A Review on a Still Hot Topic

2018 ◽  
Vol 51 (05) ◽  
pp. 200-205 ◽  
Author(s):  
René Nielsen ◽  
Lars Kessing ◽  
Willem Nolen ◽  
Rasmus Licht
Keyword(s):  
Renal Impairment ◽  
Lithium Treatment ◽  
Serum Levels ◽  
Sound Studies ◽  
Renal Outcome ◽  
Unipolar Disorder ◽  
Increased Risk ◽  
The 1960S ◽  
Stage Renal Disease ◽  
End Stage

Abstract Introduction Lithium is established as an effective treatment of mania, of depression in bipolar and unipolar disorder, and in maintenance treatment of these disorders. However, due to the necessity of monitoring and concerns about irreversible adverse effects, in particular renal impairment, after long-term use, lithium might be underutilized. Methods This study reviewed 6 large observational studies addressing the risk of impaired renal function associated with lithium treatment and methodological issues impacting interpretation of results. Results An increased risk of renal impairment associated with lithium treatment is suggested. This increased risk may, at least partly, be a result of surveillance bias. Additionally, the earliest studies pointed toward an increased risk of end-stage renal disease associated with lithium treatment, whereas the later and methodologically most sound studies do not. Discussion The improved renal outcome found in the more recent lithium studies may be a result of improved monitoring and focus on recommended serum levels (preferentially 0.6–0.8 mmol/L) as compared to poorer renal outcome in studies with patients treated in the 1960s to 1980s.

The patient with vasculitis

2015 ◽  
Author(s):  
Lorraine Harper ◽  
David Jayne
Keyword(s):  
Renal Impairment ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Drug Toxicity ◽  
Response To Therapy ◽  
Renal Outcome ◽  
Remission Induction ◽  
Renal Vasculitis ◽  
Stage Renal Disease ◽  
End Stage

The goals of treatment in renal vasculitis are to stop vasculitic activity and recover renal function. Subsequent strategies are required to prevent vasculitis returning and to address longer-term co-morbidities caused by tissue damage, drug toxicity, and increased cardiovascular and malignancy risk.Cyclophosphamide and high-dose glucocorticoids remain the standard induction therapy with alternative immunosuppressives, such as azathioprine, to prevent relapse. Plasma exchange improves renal recovery in severe presentations. Refractory disease resulting from a failure of induction or remission maintenance therapy requires alternative agents and rituximab has been particularly effective. Replacement of cyclophosphamide by rituximab for remission induction is supported by recent evidence. Methotrexate is effective in non-renal vasculitis but difficult to use in patients with renal impairment. Mycophenolate mofetil seems to be effective but there is less long-term evidence.Drug toxicity contributes to co-morbidity and mortality and has led to newer regimens with reduced cyclophosphamide exposure. Glucocorticoid toxicity remains a major problem with controversy over the rapidity with which glucocorticoids can be reduced or withdrawn.Disease relapse occurs in about 50% of patients. Early detection is less likely to lead to an adverse affect on outcomes. Rates of cardiovascular disease and malignancy are higher than in control populations but strategies to reduce their risk, apart from cyclophosphamide-sparing regimens, have not been developed. Thromboembolic events occur in 10% and may be linked to the recently identified autoantibodies to plasminogen and tissue plasminogen activator.Renal impairment at diagnosis is a strong predictor of patient survival and renal outcome. Other predictors include patient age, antineutrophil cytoplasmic antibody subtype, disease extent and response to therapy. Chronic kidney disease can stabilize for many years but the risks of end-stage renal disease are increased by acute kidney injury at presentation or renal relapse. Renal transplantation is successful with similar outcomes to other causes of end-stage renal disease.

scholarly journals P0388ABC-R ANCA STUDY ESTABLISHMENT OF AN ANATOMOPATHOLOGICAL BIOLOGICAL AND CLINICAL PROGNOSTIC SCORE IN THE MANAGEMENT OF ANCA VASCULITIS WITH RENAL IMPAIRMENT

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Florine HODIQUE ◽  
Mathilde NOUVIER ◽  
Cecile PICARD ◽  
Maud RABEYRIN ◽  
Laurent Juillard ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Renal Biopsy ◽  
Prognostic Score ◽  
Threshold Value ◽  
Published Data ◽  
Anca Vasculitis ◽  
Antibody Positivity ◽  
Renal Prognosis ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Glomerulonephritis is common in ANCA associated vasculitis (GN-AAV). There is extensive published data on the renal prognosis of these conditions. However, few authors have described predictive factors for end-stage renal disease (ESRD) in patients with GN-AAV. Many authors suggest that renal biopsy should be abandoned in patients whose diagnosis would be established by antibody positivity alone. The aim of the study was to establish a prognostic score for renal damage during ANCA vasculitis and demonstrate need for prognostic renal biopsy. Method One Hundred and eighteen patients referred to 2 french nephrology departments in Lyon between January 2003 and January 2019 were retrospectively analysed. Patients were randomly divided in 2 cohorts at a ratio of 70/30: training and validation cohorts. ESRD was defined as glomerular filtration rate (eGFR) ≤ 15mL/min/1.73m2,need of chronic dialysis or renal transplantation. Results Of the 118 patients, 38 (32.20%) developed ESRD. We identified 3 criteria associated with development of ESRD in patients with GN-AAV. One point was assigned to each criterion according to a threshold value: eGFR at the time of renal biopsy ≤ 15 mL/min; percentage of sclerotic glomeruli ≥ 11% and percentage of normal glomeruli < 20%. A new prognostic renal score was established in patients with GN-AAV. It classifies patients into 3 categories at risk of developing ESRD: low (≤ 1 point), moderate (2 points) and high (3 points). Conclusion Two of the three criteria of our score are histological. Biopsy remains, when possible, an essential tool for diagnosis and especially to predict renal prognosis of ANCA vasculitis with renal impairment.

scholarly journals Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

2007 ◽  
Vol 51 (12) ◽  
pp. 4231-4235 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Suzanne Swan ◽  
William B. Smith ◽  
Thomas C. Marbury ◽  
Gloria Dubuc-Patrick ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Normal Function ◽  
Plasma Exposure ◽  
Mild Renal Impairment ◽  
Severe Impairment ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACT This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CLCR), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CLR), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CLR and CLCR. In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of ∼45%, representing a ∼23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

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