Interpatient Variability In Clearance Research Articles

A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients.

Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. Geometric mean docetaxel clearance was 57.9L/h (GCV 78.6%) after admission of a millidose and 40.3L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

MTXPK.org: A Clinical Decision Support Tool Evaluating High-Dose Methotrexate Pharmacokinetics to Inform Post-Infusion Care and Use of Glucarpidase.

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high‐dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life‐threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3‐compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web‐based tool has the functionality to utilize individualized demographics, serum creatinine, and real‐time drug concentrations to predict the elimination profile and facilitate model‐informed administration of glucarpidase.

Measurement of Skeletal Muscle Area Improves Estimation of Aminoglycoside Clearance across Body Size.

A consistent approach to the dosing of aminoglycosides across the modern body size distribution has been elusive. We evaluated whether radiologically derived measures of body composition could explain more of the interpatient variability in aminoglycoside pharmacokinetics (PK) than standard body size metrics. This retrospective study included adult patients treated with gentamicin or tobramycin with at least three drug concentrations and computed tomography (CT) imaging available. Aminoglycoside volume and clearance (CL) estimates were computed using a two-compartment model by Bayesian analysis. Morphomic data were extracted from CT images using a custom algorithm. Bivariable and multivariable linear regression were used to assess relationships between PK parameters and covariates. A total of 335 patients were included with a median (minimum, maximum) of 4 (3, 16) aminoglycoside concentrations per patient. The median (minimum, maximum) age, height, and weight of included patients were 57 (21, 93) years, 170 (145, 203) centimeters, and 81 (42, 187) kilograms. Both standard and morphomic measures poorly explained variability in volume (R2 < 0.06). Skeletal muscle area and volume explained more of the interpatient variability in CL than weight or sex. Higher precision was observed using a modified Cockcroft-Gault equation with skeletal muscle area at L3 (R2= 0.38) or L4 (R2= 0.37) than the standard Cockcroft-Gault equation using lean (R2= 0.23), adjusted (R2= 0.23), or total (R2= 0.22) body weights. These results highlight that skeletal muscle measurements from CT images obtained in the course of care can improve the precision of aminoglycoside CL estimation over current body size scalars.

Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study.

Tranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10mg l-1 ), and perioperative blood loss. Data were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1g followed by a continuous infusion of either TXA 1g or placebo over 8h. A population pharmacokinetic study was conducted to quantify TXA exposure. In total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10mg l-1 . The model-estimated time during which the TXA concentration was above 10mg l-1 ranged from 3.3h to 16.3h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10mg l-1 or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve). In hip arthroplasty, TXA plasma concentrations were maintained above 10mg l-1 during surgery and for a minimum of 3h with a preoperative TXA dose of 1g. Keeping TXA concentrations above this threshold up to 16h conferred no advantage with regard to blood loss.

A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients.

The role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on long-term prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels <0.05 IUmL-1) undergoing elective, minor or major surgery. Retrospective data were collected on FVIII treatment, including timing and dosing, time point of FVIII sampling and all FVIII plasma concentrations achieved (trough, peak and steady state), brand of concentrate, as well as patients' and surgical characteristics. Population pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Population pharmacokinetic parameters were estimated in 75 adults undergoing 140 surgeries (median age: 48 years; median weight: 80 kg) and 44 children undergoing 58 surgeries (median age: 4.3 years; median weight: 18.5 kg). Pharmacokinetic profiles were best described by a two-compartment model. Typical values for clearance, intercompartment clearance, central and peripheral volume were 0.15 L/h/68 kg, 0.16 L/h/68 kg, 2.81 L/68 kg and 1.90 L/68 kg. Interpatient variability in clearance and central volume was 37% and 27%. Clearance decreased with increasing age (P<0.01) and increased in cases with blood group O (26%; P<0.01). In addition, a minor decrease in clearance was observed when a major surgical procedure was performed (7%; P<0.01). The developed population model describes the perioperative pharmacokinetics of various FVIII concentrates, allowing individualization of perioperative FVIII therapy for severe and moderate hemophilia A patients by Bayesian adaptive dosing.

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)

Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients ≥ 60 years old (median 66; range 60-74) had a significantly higher BuCL versus those <60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p > 0.34). Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients.

Population pharmacokinetics of farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer

PurposeThe purpose of this analysis was to develop a population pharmacokinetic model for farletuzumab, a humanized immunoglobulin (Ig)G1 monoclonal antibody (mAb) to the folate receptor alpha, which is a receptor over-expressed in ovarian cancer, but largely absent from normal tissue.MethodsIn total, 2,472 samples were included in the building of the pharmacokinetic model. Farletuzumab 12.5–400 mg/m2 had been administered via intravenous infusion to 79 patients with advanced ovarian cancer enrolled in one of the two clinical studies. Data were analyzed by a nonlinear mixed-effects modeling approach.ResultsFarletuzumab pharmacokinetics was best described by a two-compartment model with first-order (linear) elimination. In the final model, estimated values of clearance and volume of distribution of the central compartment were 0.00784 l/h and 3.00 l, respectively. Body weight was the only covariate investigated that explained inter-patient variability in clearance and the central volume of distribution. There was no effect of age, human anti-human antibodies, or concomitant chemotherapy on the pharmacokinetics of farletuzumab. Simulations showed that, when the mg/kg/week dose was maintained, steady-state exposure to farletuzumab was similar with dosing every week or every 3 weeks.ConclusionsThe pharmacokinetic parameters of farletuzumab are similar to those of other IgG mAbs. The results support weight-based dosing of farletuzumab on a weekly or 3-weekly schedule.

Effect of age on the pharmacokinetics of busulfan (Bu): An alliance study.

2533 Background: Older acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients (pts) have been excluded from myeloablative regimens including agents such as busulfan because of the potential for non-disease related morbidity and mortality. Busulfan, often used as part of myeloablative regimens, is cleared in part by glutathione–S-transferase and CYP3A4. We hypothesized that busulfan clearance (BuCL) in the elderly (&gt; 60 years) would be reduced compared to that in young patients (&lt; 60 years), thus potentially explaining differences in tolerability. Methods: AML and MDS pts in three CALGB bone marrow transplant studies across a wide age range (17-74) were treated with a conditioning regimen using IV busulfan, dosed at 12.8 mg/m2 in CALGB studies 10503 and 19808 and 6.4 mg/m2 in CALGB 100103. Blood samples were collected for determination of busulfan plasma pharmacokinetics (PK). Plasma busulfan was quantitated by LC-MS. BuCL was determined using non-compartmental modeling, and normalized to actual (ABW), ideal (IBW) and corrected (CBW) body weight (kg). Differences between age groups were examined using the Wilcoxon rank sum test. Results: A total of 185 pts were accrued and signed consent, of which 174 provided useable PK data. Twenty-nine pts ≥60 years old (median age 66.3) had a significantly higher mean BuCL vs those &lt; 60 years old (median age 49.8); BuCL 263 vs 186 mL/min, p=0.0002; BuCL/ABW 3.22 vs 2.34 mL/min/kg, p=0.0001; BuCL/IBW 3.63 vs 2.91 mL/min/kg, p=0.0035; BuCL/CBW 3.50 vs 2.70 mL/min/kg, p=0.0005. Inter-patient variability in clearance (CV%) was up to 47% in the elderly and up to 48% in young patients. Phenytoin use, a potential confounder, did not affect BuCL, regardless of weight normalization (p=0.74). Conclusions: Contrary to our hypothesis, BuCL is significantly higher in pts ≥60 years old compared to younger patients and does not explain the previously reported increase in Bu toxicity observed in the elderly.

Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients

To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between motesanib exposure and tumor response in a phase 2 study of motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer. Data from patients (n = 184) who received motesanib 125 mg once daily were used for population pharmacokinetic/pharmacodynamic modeling. Motesanib concentrations were fitted to a 2-compartment population pharmacokinetic model. Observed change in tumor size was the drug response measure for the pharmacodynamic model. Exposure measures in the pharmacokinetic/pharmacodynamic model included dose, plasma concentration profile, or steady-state area under the concentration versus time curve (AUC( ss )). A longitudinal exposure-tumor response model of drug effect on tumor growth dynamics was used. Motesanib oral clearance in patients with medullary thyroid cancer was 67% higher than in patients with differentiated thyroid cancer patients (73.7 vs. 44 L/h). Patients' disease type (medullary thyroid cancer vs. differentiated thyroid cancer) was the most important covariate for explaining interpatient variability in clearance. The objective response rates were 14 versus 2% for differentiated thyroid cancer and medullary thyroid cancer, respectively. Motesanib exposure measures (AUC( ss ) or concentration profile) were better predictors of tumor response than motesanib dose. The estimated motesanib concentration yielding tumor stasis (1.9 ng/mL) was lower than the observed trough concentrations in differentiated thyroid cancer and medullary thyroid cancer patients. Differences in motesanib pharmacokinetics likely explain the difference in tumor response observed between differentiated thyroid cancer and medullary thyroid cancer patients. The population pharmacokinetic/pharmacodynamic model provides a tool for predicting tumor response to the drug to support the dosing regimen of motesanib in thyroid cancer patients.

Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis

We conducted population anticoagulant pharmacodynamic analysis for patients administered the low-molecular weight heparin tinzaparin. Data from 425 patients (2,631 observations) who participated in 2 Phase III clinical studies were utilized in an analysis based on a pharmacodynamic structural model of anti-Xa activity using non-linear mixed effects modeling techniques. Anti-Xa activity from patients participating in a multicenter, randomized, double-blind clinical trial comparing intravenous once daily subcutaneous tinzaparin (175 IU/kg) with heparin for the treatment of deep vein thrombosis (DVT) was first examined using a 2-compartment model with first-order absorption and endogenous anti-Xa activity. Covariates included renal function, body weight, age, gender, race, obesity, concomitant administration of warfarin, and diabetes. The population estimates and 90% confidence intervals (CI) for oral clearance (CL) and apparent volume of distribution of the plasma compartment (Vc) were 0.0176 l/h/kg (CI = 0.012-0.023) and 0.098 l/kg (CI = 0.088 - 0.109), respectively. The elimination half-life was 3.9 h (CI = 2.5-5.2). These estimates are similar to findings in healthy volunteers. The inter-patient variability in clearance was related to plasma creatinine and percent above ideal body weight. Clearance decreased by 22% for patients with severe renal function impairment (creatinine clearance < 30 ml/min), and by about 25% in obese patients (BMI > 30 kg/m2). Changes of these magnitudes were not clinically important in pooled clinical trial safety and efficacy analyses. Body weight was not a significant covariate in the model supporting the observations in earlier well-defined trials, where tinzaparin was dosed on a weight basis (lU/kg). Clearance was not influenced by age, race or gender. The same model was applied to data obtained from a prospective, randomized, double-blind clinical trial comparing tinzaparin (4,500 IU) to enoxaparin (40 mg) once daily in patients undergoing total hip replacement. Model parameters were similar to those previously obtained supporting the extension of these results across dose and indication. Population analysis in patients with disease and heterogeneity indicated similar pharmacodynamics as in volunteers, supporting weight-based dosing and identified the dependence of clearance on obesity and severe renal function, although the magnitude of these effects are probably not clinically significant.

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

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. 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. 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) x 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. 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.

Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice. Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006. Seven classes of drugs were chosen, including gastric proton pump inhibitors, histamine H(2)-receptor antagonists, benzamide-type gastroprokinetic agents, selective 5-HT(3) receptor antagonists, fluoroquinolones, macrolide antibiotics and azole antifungals. They showed significant differences in metabolic profile (i.e., the fraction of drug metabolized by cytochrome P450 (CYP), CYP reaction phenotype, impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential). Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues. Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy. The relevant CYP knowledge helps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

Evaluation of an Alternate Dosing Strategy for Cisplatin in Patients With Extreme Body Surface Area Values

The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average +/- 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value < or = 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value > or = 2.05 m2. CONCLUSION Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (< or = 1.65 m2; 1.66 m2 to 2.04 m2; > or = 2.05 m2) are recommended.

Covariate Effects on the Apparent Clearance of Tacrolimus in Paediatric Liver Transplant Patients Undergoing Conversion Therapy

To analyse the influence of covariates on the apparent clearance (CL) of tacrolimus in paediatric liver transplant recipients being converted from cyclosporin to tacrolimus. Retrospective modelling study. 18 children, 13 girls and 5 boys, aged 4 months to 16 years (median 9.1 years) who required conversion to tacrolimus because of acute or chronic rejection or cyclosporin toxicity. 287 whole-blood tacrolimus concentrations from therapeutic drug monitoring were used to build a nonlinear mixed-effects population model (NONMEM program) for the apparent clearance of tacrolimus. Variables considered were age, total bodyweight (TBW), body surface area (BSA), time after initiation of treatment (T), gender, haematocrit (Hct), albumin (Alb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gammaGT), alkaline phosphatase (ALP), bilirubin (BIL), creatinine clearance (CL(CR)) and dosage of concomitant corticosteroids (EST). TBW, T, BIL and ALT were the covariates that displayed a significant influence on CL according to the final regression model: CL (L/h) = 10.4(TBW/70)3/4 x e(-0.00032 T) x e(-0.057 BIL) x (1 - 0.079 ALT). With this model, the estimates of the coefficients of variation were 24.3% and 29.5% for interpatient variability in CL and residual variability, respectively. The proposed model for tacrolimus CL can be applied for a priori dosage calculations, although the results should be used with caution because of the unexplained variability in the CL. We therefore recommended close monitoring of tacrolimus whole blood concentrations, especially within the first months of treatment. The best use of the model would be its application in dosage adjustment based on therapeutic drug monitoring and the Bayesian approach.

Population pharmacokinetics of aminoglycoside antibiotics in patients with cystic fibrosis.

The population pharmacokinetics of gentamicin and tobramycin were investigated in a group of 51 young adults with cystic fibrosis. Their ages ranged from 14-35 years, weights from 38-82 kg, and 27 of the patients were female. None of the patients had renal impairment, but 3 patients were treated in the intensive therapy unit (ITU) during one of their courses of therapy. Data comprised 219 courses of therapy and 544 concentrations (mean: 11 per patient). Concentration-time data were analyzed using a nonlinear mixed-effects model package (NONMEM) and were best described by a one-compartment model. Factors identified as potentially influencing aminoglycoside pharmacokinetics were added in a stepwise fashion and the best model found that drug clearance and volume of distribution were related to body surface area and admission to ITU. The mean population estimates were a clearance of 2.89 L/hr/m2 and a volume of distribution of 9.21 L/m2 with a 60% increase in patients who were admitted to ITU. Interpatient variability in clearance and volume were 14% and 8%, respectively. The results suggested that a dose of 120 mg/m2 should achieve an average 1 hour postdose peak of 10 mg/L and trough of <1 mg/L and that higher doses might be required in ITU patients.

Valproate population pharmacokinetics in children.

A population analysis of the kinetics of valproic acid (VPA) in children with epilepsy was performed in order to characterize the covariates which influence VPA clearance (CL). A total of 770 steady-state serum concentration samples was analysed. These were collected during VPA therapy from 255 children, aged 0.1-14 years and weighting 4-74 kg. Age, total body weight (TBW), VPA daily dose, sex and comedication with carbamazepine (CBZ) were considered as covariates. Population analysis was made with NONMEM program, assuming a one-compartment model, fixing the VPA absorption rate, bioavailability and distribution volume at values found in the literature. The results of the population pharmacokinetics analysis were validated in a group of 45 epileptic patients. The final regression model for VPA clearance, that included TBW (kg), daily dose (mg/kg) and CBZ comedication as covariates with a significant influence on this parameter, was as follows: CL (L/h) = 0.012 TBW0.715 DOSE0.306(1.359 CBZ). The coefficient of variation for interpatient variability in CL was 21.4% and the residual variability estimated was 23.9% for a concentration of 65 mg/l. In order to estimate the predictive performance of the selected final model, predictions of the VPA serum concentrations were calculated and compared with VPA measured concentrations in the validation group. This assessment revealed an important improvement in the predictive performance of VPA concentrations in comparison with the basic model that did not include any covariates (root squared mean error: 19.50 vs. 39.73 mg/l). A population pharmacokinetic model is proposed to estimate the individual CL for paediatric patients receiving VPA in terms of patient's dose, weight and concomitant CBZ, in order to establish a priori dosage regimens.

Effects of demographic variables on vorozole pharmacokinetics in healthy volunteers and in breast cancer patients.

Vorozole (VOR) is a selective nonsteroidal inhibitor of the cytochrome P450-dependent aromatase that catalyzes the conversion of androgens to estrogens. It is currently being developed as a therapeutic agent in the endocrine treatment of postmenopausal women with breast cancer. This work was aimed to explore the effects of demographic and other variables on VOR pharmacokinetics. VOR plasma concentration-time data were obtained in healthy volunteers and in breast cancer patients after the oral administration of 2.5 mg of VOR as a single dose or once daily. The data obtained in 6 formal pharmacokinetics (PK) studies with frequent plasma sampling were included in the data base (84 healthy male and female volunteers and 13 breast cancer patients). Also included were data from 2 clinical efficacy trials involving 286 breast cancer patients who were treated for several months (1 sample per visit, up to 14 samples/patient). The nonlinear mixed-effect modeling (NONMEM) approach was applied. The two-compartment linear PK model with first-order absorption parameterized in terms of apparent clearance (CL), apparent central and peripheral volumes of distribution (Vc and Vp, respectively), apparent distributional flow (Q), and absorption constant (ka) was used. A population model was developed using data from formal PK studies. The final estimates of fixed and random effect parameters were obtained using both formal study data and clinical-efficacy trial data. The typical CL value obtained after a single dose was lower in patients (4.8 l/h) as compared with healthy volunteers (8.6 l/h) and did not depend on gender. The multiple- to single-dose ratio was 0.76. CL was constant over ages of up to 50 years and then decreased slightly (0.047 l/h per year). The typical CL value did not depend on any demographic variable related to body size (total body weight, WT; body surface area; lean body mass). Q and Vc were proportional to WT (0.17 l h(-1) kg(-1) and 0.43 l/kg, respectively). Vp was also proportional to WT and was higher in women as compared with men (0.64 and 0.40 l/kg, respectively). The same was true for the apparent steady-state volume of distribution. No effect of race or the duration of therapy (0.5-28 months) was seen. The unexplained variability in CL and the residual variability in VOR plasma concentrations were 39% and 28% (coefficient of variation), respectively. Healthy volunteer/patient, single/multiple dosing differences, and age were identified as the fixed effects influencing the CL of VOR. WT was the main determinant of distributional PK parameters. The peripheral and steady-state volumes of distribution were gender-dependent. In view of the relatively high degree of residual interpatient variability in CL, the slight effect of age on it is unlikely to be clinically significant.

Pharmacokinetics of continuous infusions of fentanyl in critically ill children.

To determine the pharmacokinetics of fentanyl when used as a long-term continuous infusion for sedation/analgesia in mechanically ventilated critically ill infants and children. Prospective, case series. A university hospital pediatric intensive care unit (ICU). Nineteen mechanically ventilated infants and children (0.05 to 14 yrs of age) who received continuous infusions of fentanyl for > 24 hrs. None. Plasma concentrations of fentanyl were measured 1 hr after a loading dose and at various intervals during and after the infusions were discontinued. Noncompartmental pharmacokinetic variables, total body clearance, volume of distribution at steady state, and terminal elimination half-life were calculated. Clinical sedation scores, ventilatory settings, pupillary size and reactivity, and patient demographics were recorded. After the use of fentanyl by long-term infusion, the volume of distribution at steady state was increased 15.2 L/kg (range 5.1 to 30.5) and the terminal elimination half-life was prolonged 21.1 hrs (range 11.2 to 36.0) compared with previous studies. Clearance was rapid and consistent with other studies. There was a large interpatient variability in clearance that was age dependent. Clearance did not appear to increase over time. Total body clearance of fentanyl is highly variable and it should be dosed to effect. Patients seen in a pediatric ICU may require a ten-fold variability in fentanyl infusion rates to achieve similar levels of sedation.

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.