Interpatient Variability (interpatient + variability)

Distribution by Scientific Domains

Selected Abstracts

Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients

Christa E. Nath
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The pharmacokinetics of oral busulphan given four times daily has been extensively studied. , Large inter- and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring. , However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6-h dosing interval, due to late absorption in some patients. , Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose. WHAT THIS STUDY ADDS , Inter- and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable. , Children with immune deficiencies, in particular, have widely variable exposure. AIM To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. METHODS Busulphan (120 mg m,2, 130 mg m,2 or 3.2 mg kg,1) was administered over median 2.1 h. Blood samples (4,10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration,time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m,2 dose in 13 children who had busulphan pharmacokinetic monitoring. RESULTS Clearance of i.v. busulphan in 40 children was 4.78 2.93 l h,1 (% CV 61%), 0.23 0.08 l h,1 kg,1 (% CV 35%) and 5.79 1.59 l h,1 m,2 (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h,1) and CL (l h,1 kg,1), but not with CL (l h,1 m,2). AUC normalized to the 130 mg m,2 dose ranged from 14.1 to 56.3 mg l,1.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h,1 m,2) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. CONCLUSIONS There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h,1 m,2) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required. [source]

Interindividual variation of serum haloperidol concentrations in Japanese patients , clinical considerations on steady-state serum level,dose ratios

E. Yukawa
Summary Objective:, Marked interpatient variability in haloperidol (HAL) level,dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations. Objective:, To investigate the effect of dose, age, total body weight and co-medication on steady-state HAL L/D ratios. Method:, Retrospective analysis of dose and HAL blood level data from 168 patients. Results:, The HAL L/D ratio decreased curvilinearly with increasing daily dose of HAL. The patients treated with concomitant antiparkinsonian drugs showed a mean HAL L/D ratio that was 249% higher than those without antiparkinsonian drugs. The patients treated with concomitant antiepileptic drugs showed a mean HAL L/D ratio that was 272% lower than those without antiepileptic drugs. The mean HAL L/D ratio of patients treated with concomitant CYP2D6 substrates was not significantly different from those without CYP2D6 substrates. Conclusion:, There is a wide interindividual variability in blood levels of HAL in patients given the same dose. Routine monitoring of HAL serum level is useful, especially in patients who require associated antiepileptic and/or antiparkinsonian medication. [source]

Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long-term methotrexate treatment,

Lisa K. Stamp
Objective Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) in the management of rheumatoid arthritis (RA). MTX is transported into cells, where additional glutamate moieties are added and it is retained as MTX polyglutamates (MTXGlu [referred to as a group as MTXGlun]). There is large interpatient variability in MTXGlun concentrations. This study was undertaken to determine nongenetic factors that influence red blood cell (RBC) MTXGlun concentrations in patients receiving long-term stable low-dose oral MTX. Methods One hundred ninety-two patients receiving long-term oral MTX for the treatment of RA were recruited. Trough MTXGlun concentrations were measured by high-performance liquid chromatography. Univariate analysis was performed to determine variables influencing MTXGlun concentrations. Backward stepwise multivariate regression analysis was done to determine variables that affect individual MTXGlun concentrations; variables with P values of <0.1 in the univariate analysis for any MTXGlun were included. Results Univariate analysis revealed that increased age, lower estimated glomerular filtration rate (GFR), higher MTX dosage, longer duration of MTX treatment, and use of prednisone were associated with significantly higher MTXGlun concentrations. Smokers had significantly lower concentrations of MTXGlu3, MTXGlu3,5, and MTXGlu1,5. Sex, rheumatoid factor and anti,cyclic citrullinated peptide status, RBC folate level, and body mass index had no significant effect on MTXGlun levels. Concomitant use of other DMARDs was associated with lower MTXGlu2 levels, and treatment with nonsteroidal antiinflammatory drugs was associated with lower MTXGlu3 and MTXGlu1,5 concentrations. Multivariate regression analysis revealed that age, MTX dosage, and estimated GFR were the major determinants of MTXGlun concentrations. Conclusion Large interpatient variability in MTXGlun concentrations can be explained, at least in part, by a combination of factors, particularly age, MTX dosage, and renal function. There are complex interactions between smoking, RBC folate levels, and concentrations of MTXGlun. [source]

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis,

Judith M. Dalrymple
Objective There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1,5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1,5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1,5 to become undetectable and the half-life of elimination of RBC MTXGlu1,5 in patients ceasing treatment with oral MTX. Methods Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1,5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method. Results The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1,5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1,5 ranged from 1.2 weeks to 4.3 weeks. Conclusion There is wide interpatient variability of RBC MTXGlu1,5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1,5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered. [source]

Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patients

Rob Ter Heine
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre-treated for HIV-infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS , We investigated the steady-state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment. AIM To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l,1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK,PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance. [source]

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

Marie Antignac
What is already known about this subject , ,In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. , ,Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients. What this study adds , ,Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus. , ,Clearance was modelled and days postoperation and corticosteroids dose were significant covariates. Aims The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics. Methods The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring. Results A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 0.2 l h,1. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 0.5 days, with a maximal value of 5.6 l h,1. Moreover clearance increased by approximately 1.6 fold (range 0.5,1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 13 l kg,1) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F. Conclusions The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance. [source]

Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency

Peak M. Mah
Summary objective, The objective of this study was to examine the variables determining hydrocortisone (HC) disposition in patients with adrenal insufficiency and to develop practical protocols for individualized prescribing and monitoring of HC treatment. design and patients, Serum cortisol profiles were measured in 20 cortisol-insufficient patients (0900 h cortisol < 50 nmol/l) given oral HC as either a fixed or ,body surface area-adjusted' dose in the fasted or fed state. Endogenous cortisol levels were measured in healthy subjects. Pharmacokinetic analysis was performed using P-Pharm software, and computer simulations were used to assess the likely population distribution of the data. results, Body weight was the most important predictor of HC clearance. A fixed 10-mg HC dose overexposed patients to cortisol by 63%, whereas weight-adjusted dosing decreased interpatient variability in maximum cortisol concentration from 31 to 7%, decreased area under the curve (AUC) from 50 to 22% (P < 005), and reduced overexposure to < 5%. Food taken before HC delayed its absorption. Serum cortisol measured 4 h after HC predicted cortisol AUC (r2 = 078; P < 0001). conclusions, We recommend weight-adjusted HC dosing, thrice daily before food, monitored with a single serum cortisol measurement using a nomogram. This regimen was prospectively examined in 40 cortisol-insufficient patients, 85% of whom opted to remain on the new thrice-daily treatment regimen. [source]