Initial Dosing Regimen Research Articles

Population Pharmacokinetics of Metformin in Mexican Patients with Type 2 Diabetes Mellitus

The aim of this study was to develop a Population Pharmacokinetic Model (PPM) for Metformin and to determine the influence of physiologic covariates on its pharmacokinetic variability in patients with Type 2 Diabetes Mellitus (T2DM). Ninety-nine patients with T2DM were included in the study. The clinical and pharmacokinetic data of 81 patients were used to build the population model and validated in others 18 patients. All patients received Metformin at a dose of 500-850 mg every 8 h. Blood samples were obtained at 2, 4, 6 or 8 h after drug administration, levels of drug were assayed by high performance liquid chromatography. The PPM was built using a nonlinear mixed effect program. The PPM was fitted to an open one compartment model, Ka = 2.22 h‾1 (CV61.5%), CL/F = 26.4 L h‾1 (CV 50.2%) and V/F = 365 L (CV 34.1%). Creatinine clearance (CLcr) and Lean Body Weight (LBW) correlated significantly with CL/F and V/F, respectively. The inclusion of these covariates in the basic model improved significantly the prediction performance as evaluated by the log-likelihood function. The final model was: CL/F = 16.6×exp (0.00546×CLcr), V/F = 209×exp (0.0112×LBW), with CV of 47 and 31.2%, respectively. In the PPM of metformin in Mexican patients with T2DM here described, the covariates, LBW and CLcr had a significant influence on interindividual variability of V/F and CL/F. Model evaluation suggested that the PPM is robust and its parameters were estimated with good precision. The model may be useful for clinician to design a rational initial dosage regimen in this patient population.

Evaluation of initial methadone dosing for prevention of iatrogenic opioid abstinence syndrome in children

Methadone is commonly prescribed for prevention of iatrogenic opioid abstinence syndrome (IOAS) in critically ill children. However, there is a paucity of data on the recommended initial dosage requirements. Data was retrospectively collected from January--December 31, 2008 and included demographics, methadone regimen, and IOAS symptoms. The primary objective was to determine the initial methadone dosing utilized (i.e., mg/kg/day) and the impact that this had on the number of dosage changes required for prevention of IOAS in patients < 18 yr within 72 hr following discontinuation of opioid continuous infusion (CI). Secondary objectives included a comparison of methadone dose changes within 72 hr of intravenously opioid discontinuation and opioid CI requirements based on initial doses above and below the median level (i.e., mg/kg/day). Between-group analysis was performed using descriptive and inferential statistics. A step-wise regression was employed to assess relationships between the initial dose (mg/kg/day) and several independent variables. Fifty-five patients were included for analysis. The median initial dose was 0.84 mg/kg/day. The "low-dose" group included patients receiving < 0.84 mg/kg/day (n = 27); the "high-dose" group included patients receiving ≥; 0.84 mg/kg/day (n = 28). The majority of patients (81.8%) received doses every 6 hr. Twenty-three patients (41.8%) developed IOAS and required an increase in dose while six patients (10.9%) required a decrease. No significant differences were found between groups. The cumulative and peak fentanyl CI doses were the only significant predictors of total mg/kg/day dose of methadone (P < 0.01). The initial methadone dosage regimens varied greatly in our patients. Approximately half required a change in their methadone dose. Based on our findings and a review of the literature, there is not a one-size fits all approach for determination of the initial methadone dose. Adoption of a consistent monitoring tool should be utilized for all children across the continuum of care to prevent IOAS and the over-sedation noted with excessive methadone dosing.

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Pediatric Assessment of Vancomycin Empiric Dosing (PAVED): a Retrospective Review.

Pediatric studies and anecdotal experience suggest that current empiric vancomycin dosing does not reach serum trough concentration targets of at least 10 mg/L for uncomplicated infections or 15-20 mg/L for serious or complicated infections. This study reviewed vancomycin dosing and serum concentrations to (i) determine the proportion of patients who reached initial target concentrations; (ii) describe pharmacokinetic parameters; and (iii) compare patient-specific area-under-the-curve (AUC) values to population estimates using the Rodvold equation. Following ethics approval, data were extracted from medical records of 200 patients aged 1 month-18 years, who received intravenous (IV) vancomycin and had at least two pharmacokinetically evaluable serum concentrations. Trough vancomycin concentrations of 10-15 and 15-20 mg/L were achieved in 25 (29%) and 2 (2%) patients receiving vancomycin 15 mg/kg IV every 6 h (q6 h) and 22 (20%) and 9 (8%) patients receiving vancomycin 20 mg/kg IV every 8 h (q8 h), respectively. Patients were stratified into four age groups (1 month-1 year, 1-6 years, 6-13 years and 13-18 years). Median (IQR) pharmacokinetic parameters were elimination rate constant 0.25 (0.09), 0.29 (0.07), 0.24 (0.10) and 0.22 (0.07) h(-1); volume of distribution 0.56 (0.20), 0.61 (0.21), 0.47 (0.26) and 0.49 (0.22) L/kg; and half-life 2.8 (1.1), 2.4 (0.5), 2.9 (1.1) and 3.2 (1.0) h, respectively. Median (IQR) AUCs were 458 (170), 338 (132), 478 (215) and 513 (179) mg h/L and population-estimated AUCs were 67 (44), 108 (70), 299 (102) and 454 (103) mg h/L (p < 0.05 for all groups). Based on these findings, we recommend vancomycin 70 and 90 mg/kg/day divided q6 h for troughs of 10-15 and 15-20 mg/L, respectively (patients 1 month-6 years) and 60 mg/kg/day divided q8 h and 70 mg/kg/day divided q6 h, respectively (patients >6 years) to undergo further testing as initial dosing regimens. Furthermore, population estimates grossly underestimate vancomycin AUC in patients 1-18 years old and thus patient-specific parameters are required.

Development and Assessment of a Nomogram to Propose the Initial Dosage Regimen of a Meropenem Infusion Based on Serum Creatinine and Age Using a Monte Carlo Simulation.

A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y=-0.4676x+80.281, R(2)=0.4888; female: y=-0.4373x+77.502, R(2)=0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6±3.1 kg, BW 41.7±3.5 kg, p=0.93; female: e-BW 39.5±2.1 kg, BW 39.5±3.7 kg, p=0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n=28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr.

Predictive performance of Vancomycin population pharmacokinetic models in Iranian patients underwent hematopoietic stem cell transplantation

Objective:Many hematopoietic stem cell transplantation (HSCT) patients receive vancomycin empirically during febrile neutropenia. There are several models for estimation of vancomycin pharmacokinetic parameters and calculation of initial dosing regimen accordingly. However, the performance of these methods in HSCT patients remained to be evaluated. The aim of the study was to determine which of the vancomycin population pharmacokinetic methods best fit Iranian HSCT patients.Methods:In order to evaluate predicted performance of seven vancomycin population pharmacokinetic models, the pharmacokinetic parameters of patients were estimated using each model's equations. Then the predicted steady-state trough vancomycin concentration was calculated based on each model's parameters and using a formula based on Sawchuk–Zaske method. The predicted steady-state trough vancomycin concentration and the real measured concentrations were compared to see which method was the most precise and least biased using mean squared error (MSE) and mean prediction error (ME) respectively.Findings:Forty-six patients (65% men) were included in the study. Calculated metrics showed a range of 38% under-prediction bias with Rodvold to 34% over-prediction bias with Matzke and Burton models. Birt and revised Burton methods showed no significant bias (ME [95% confidence interval (CI)]: –0.067 [–0.235–0.101] and 0.066 [–0.105–0.238]). Birt and revised Burton were not different significantly considering MSE (95% CI) of 0.385 (0.227–0.544) and 0.401 (0.255–0.546), respectively. Comparisons of precision with naive predictors revealed a delta MSE (95% CI) of –0.128 (–1.379–1.890) for Birt and 0.026 (–0.596–0.940) for revised Burton models.Conclusion:Although the Birt and Burton revised methods performed well, none of the studied models showed acceptable performance to be implemented as a routine method for initial dose calculation in HSCT patients. A vancomycin pharmacokinetic model specific for this high-risk subpopulation of Iranian patients should be designed and validated.

Initial dosing regimen of vancomycin to achieve early therapeutic plasma concentration in critically ill patients with MRSA infection based on APACHE II score.

It is essential to assure the efficacy of antimicrobials at the initial phase of therapy. However, increasing the volume of distribution (Vd) of hydrophilic antimicrobials in critically ill patients leads to reduced antimicrobial concentration in plasma and tissue, which may adversely affect the efficacy of that therapy. The aim of the present study was to establish a theoretical methodology for setting an appropriate level for initial vancomycin therapy in individual patients based on Acute Physiology and Chronic Health Evaluation (APACHE) II score. We obtained data from patients who received intravenous vancomycin for a suspected or definitively diagnosed Gram-positive bacterial infection within 72h after admission to the intensive care unit. The Vd and elimination half-life (t 1/2) of vancomycin values were calculated using the Bayesian method, and we investigated the relationship between them and APACHE II score. There were significant correlations between APACHE II scores and Vd/actual body weight (ABW), as well as t 1/2 (r=0.58, p<0.05 and r=0.74, p<0.01, respectively). Our results suggested that the Vd and t 1/2 of vancomycin could be estimated using the following regression equations using APACHE II score.[Formula: see text] [Formula: see text]We found that APACHE II score was a useful index for predicting the Vd and t 1/2 of vancomycin, and used that to establish an initial vancomycin dosing regimen comprised of initial dose and administration interval for individual patients.

Predictive performance of gentamicin dosing nomograms

BackgroundSeveral nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients.MethodsGentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with “other” infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated.ResultsGentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%–72.3% vs 4.3%–45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients.ConclusionGentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.

Triazole antifungal agents: practice guidelines of therapeutic drug monitoring and perspectives in treatment optimization

Antifungal triazole agents (fluconazole, voriconazole, itraconazole and posaconazole) are widely used for the management of invasive fungal infections (IFI). These drugs are indicated both for the prophylaxis and treatment of IFI, particularly in candidiasis and aspergillosis, major cause of mortality in immunocompromised patients. Due to a large interindividual pharmacokinetic variability leading to sub-therapeutic or toxic concentrations and to concentration-efficacy and/or -toxicity relationships, therapeutic drug monitoring (TDM) of antifungal triazole is fully justified. This review provides an overview of literature based data that confirm the usefulness of such TDM and its level of evidence as well as the practical guidelines for its implementation. In addition, we discuss the interest of new tools to improve the clinical management of IFI, such as genotyping tests optimizing initial voriconazole dosing regimen or the development of a new solid oral tablet of posaconazole improving its bioavailability and limiting absorption disorders.

Comparison of initial loading doses of 5 mg and 10 mg for warfarin therapy

CONTEXT: The question of what is the best loading dosage of warfarin when starting anticoagulant treatment has been under discussion for ten years. We were unable to find any comparative studies of these characteristics conducted here in Brazil. OBJECTIVE: To compare the safety and efficacy of two initial warfarin dosage regimens for anticoagulant treatment. METHODS: One-hundred and ten consecutive patients of both sexes, with indications for anticoagulation because of venous or arterial thromboembolism, were analyzed prospectively. During the first 3 days of treatment, these patients were given adequate heparin to keep aPTT (activated partial thromboplastin time) between 1.5 and 2.5, plus 5 mg of warfarin. From the fourth day onwards, their warfarin doses were adjusted using International Normalized Ratios (INR; target range: 2 to 3). This prospective cohort was compared with a historical series of 110 patients had been given 10 mg of warfarin on the first 2 days and 5 mg on the third day with adjustments based on INR thereafter. Outcomes analyzed were as follows: recurrence of thromboembolism, bleeding events and time taken to enter the therapeutic range. RESULTS: Efficacy, safety and length of hospital stay were similar in both samples. The sample that were given 10 mg entered the therapeutic range earlier (means: 4.5 days vs. 5.8 days), were on lower doses at discharge and had better therapeutic indicators at the first return appointment. CONCLUSIONS: The 10 mg dosage regimen took less time to attain the therapeutic range and was associated with lower warfarin doses at discharge and better INR at first out-patients follow-up visit.

Determination of the Most Influential Sources of Variability in Tacrolimus Trough Blood Concentrations in Adult Liver Transplant Recipients: A Bottom-Up Approach

Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (P(fat)), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLi(typ)), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fu(p)), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fu(p), CLi(typ), bioavailability, body weight, hematocrit, CYP3A5 polymorphism, P(fat), and CYP3A4 inhibitory drug-drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient's hematocrit and body weight are proposed.

Identification Of Patients (pts) With Chronic Myeloid Leukemia (CML) At High Risk Of Artery Occlusive Events (AOE) During Treatment With The 2nd Generation Tyrosine Kinase Inhibitor (TKI) Nilotinib, Using Risk Stratification For Cardiovascular Diseases (CVD)

Background Nilotinib is approved for use in pts with CML after failure of imatinib and in newly diagnosed CP-CML. However, several studies report a nilotinib-associated risk of AOE, especially in pts with preexisting risk factors for CVD. Since CVD are a major cause of disability and death worldwide and result from complex interactions between multiple risk factors, we aimed at determining whether CVD risk estimation using the 2012 European Society of Cardiology (ESC) classification could be useful to identify patients at high risk of AOE during nilotinib therapy. Methods Pts (n=75) treated with nilotinib upfront or after failure of prior TKI at our institution were included provided that baseline risk factors for CVD and prior history of established CVD could be retrospectively collected. Risk factors included age, tobacco use, diabetes mellitus (DM), arterial hypertension (AH), dyslipidemia and increased body mass index (BMI). Patients were categorized into 2 groups according to ESC 2012 classification: low/moderate (L/M) and high/very high (H/VH) CVD risk. H/VH included pts with any of the following: established CVD, DM, severe AH, familial dysplipidemia or a SCORE (systematic coronary risk evaluation project) ≥5%. Results At nilotinib initiation, median age was 51 years (19-76), 41 pts (54.7%) were males. Nilotinib was given upfront in 28 pts (37%) and after failure of imatinib or dasatinib following imatinib in 47 pts (63%). Median time from diagnosis was 1 month (0.3-4) in the former group and 25 months (2-130) in the latter. Median duration of TKI exposure prior to nilotinib in the latter group was 22 months (0.4-91). Initial nilotinib dosing regimen was 400mg BID in 42 pts (56%) and 300mg BID in 33 pts (44%). Median duration of nilotinib treatment of 28 months (3-76) and median follow-up was 30 months (3-77). At baseline, medical history revealed H/VH risk category in 15 pts (20%) including established CVD in 6 pts (8%) (all diagnosed before CML), DM in 10 pts (13.3%), severe AH in 1 pt (1.3%), familial dyslipidemia in 1 pt (1.3%) and a SCORE ≥5% in 2 pts (2.6%). Median number of CVD risk factors was 1 (0-6) including age ≥ 45 years in men and ≥ 55 years in women in 37 pts (49.3%), active smoking or ceased during the previous year in 12 pts (16.7%), DM in 10 pts (13.3%), AH in 14 pts (18.7%), dyslipidemia in 10 pts (13.3%) and BMI ≥ 25 kg/m2in 20 pts (38.6). Nilotinib was discontinued in 23 pts (30.7%) due to adverse events (10 pts), resistance (7 pts), TKI discontinuation study (4 pts) or death (2 pts). AOE occurred in 12 pts after a median duration of nilotinib treatment of 24 months (9-47). AOE included myocardial infarction (MI) or coronary heart disease (CHD) (n=3), cerebrovascular events (CeVD) (n=3) and peripheral artery disease (PAD) (n=6). Overall, the cumulative incidence of AOE was 2.91% (95% CI: 0.74-11.42) by 12 months, 9.81% (95% CI: 4.57-21.08) by 24 months, 19.29 (95% CI: 10.77-34.56) by 36 months and 27.7% (95% CI: 16.2-47.35) by 48 months (discontinuation of nilotinib and death as competing risks). Cumulative incidence of AOE by 48 months was 72.22% (95% CI: 47.46-100) in the H/VH group and only 12.13% (95% CI: 4.32-34.08) in the L/M group. Log Rank comparison of Kaplan Meier analysis of 48-month survival without AOE showed a significant difference between the 2 groups (27.78% (95% CI: 0-58.9) versus 84.38% (95% CI: 67.04-100) p=0.0001). Sensitivity of the ESC classification in nilotinib-treated patients was 67% and specificity 89%. It is important to note that all pts with a history of AOE had recurrent AOE on nilotinib. Nilotinib was discontinued in 11 pts with AOE after a median time of 288 days (1-688), 7 pts had recurrent or worsening AOE before nilotinib discontinuation and 2 pts died from AOE. Conclusions In our retrospective study, CVD risk estimation according to the 2012 ESC classification reveals that pts who belong to the H/VH risk group at baseline are at very high risk of AOE during nilotinib therapy. These findings now need to be validated in a prospective fashion. Nevertheless, we readily recommend that assessment of CVD risk should be performed in all pts considered for nilotinib therapy. Alternative TKI may be chosen whenever possible in pts at H/VH risk of CVD. In those treated with nilotinib, CVD risk should be reassessed throughout therapy and risk factors should be tightly controlled according to current guidelines. Disclosures: Rea: BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; ARIAD: Honoraria; Teva: Honoraria. Messas:Novartis: Honoraria.

Prospective Analysis Of Plasma Cholesterol and Triglycerides In Patients (pts) With Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) During Treatment With The 2nd Generation Tyrosine Kinase Inhibitor (TKI) Nilotinib

BackgroundNilotinib is approved for use in pts with CML after failure of imatinib and in newly diagnosed CP-CML. In the ENESTnd trial, 1st line nilotinib was associated with a higher frequency of hypercholesterolemia than imatinib. Moreover, several studies reported a nilotinib-associated risk of artery occlusive disease (AOD). In ENESTnd, pre-existing treatment for dyslipidemia did not preclude pts from enrolment. To avoid this pitfall and to determine which cholesterol fractions are affected and whether triglycerides (TG) are modified, we prospectively studied the plasma lipid profile of nilotinib-treated pts without drug treatment for dyslipidemia. MethodsPts (n=25) in our center with CP-CML either newly diagnosed or after failure of imatinib were proposed 1st or 2nd line nilotinib provided that neither very high risk for fatal cardiovascular disease (CVD) nor nilotinib-resistant ABL kinase domain mutation were present at baseline. Pts with drug treatment for dyslipidemia at baseline were excluded from this study. Total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and TG were measured prior to the start of nilotinib and at 3, 6, 9 and 12 months. Fasting glucose (FG) and glycosylated hemoglobin (HbA1C) were also measured. Results are shown as medians (min-max). ESC/EAS 2012 guidelines were used to determine CVD risk categories and for the management of dyslipidemias. ResultsMedian age at nilotinib initiation was 52 years (19-69), 13 were males (52%). Sokal risk group was low in 11 pts (44%), intermediate in 11 (44%) and high in 3 (12%). Nilotinib was given upfront in 20 pts (80%) and after 1st line imatinib in 5 pts (20%). Median time from diagnosis was 0.8 month (0.4-4.3) in the former and 15.7 months (2.5-47.9) in the latter. Initial nilotinib dosing regimen was 300mg BID in 22 pts (88%) and 400mg BID in 3 pts (12%). Baseline CVD risk factors included age ≥ 45 years in men and ≥ 55 years in women in 33 pts (52%), active smoking or ceased during the previous year in 6 pts (24%), body mass index (BMI) ≥ 25 kg/m2in 14 pts (56%), hypertension in 1 pt (4%), type 2 diabetes mellitus (DM) in 1 pt (4%). Two pts were discovered pre DM. The CVD risk was low in 12 pts (48%), moderate in 11 pts (44%) and high in 2 pts (8%).At baseline, no pt required drug intervention by lipid lowering agents based on LDL-C, 11 pts (44%) had low HDL-C (≤0.4g/L) and 7 (28%) had high TG (≥1.5g/L). Median FG and HBA1C were 0.88g/L (0.63-1.26) and 5.5% (4.7-6.5), respectively. All pts were given lifestyle medical advice. At M3, TC, LDL-C and HDL-C had increased by a mean of 26.9%, 31.8% and 36.3%, respectively. Median TC at baseline and M3 was 1.84g/L (1.17-2.74) and 2.27g/L (1.08-3.62) (p<0.0001). Median LDL-C at baseline and M3 was 1.13g/L (0.69-2.02) and 1.45g/L (0.68-2.7) (p=0.00012). Median HDL-C at baseline and M3 was 0.42g/L (0.16-0.77) and 0.55g/L (0.27-0.99) (p<0.0001). Only 3 pts (12%) had low HDL-C at M3. In contrast, TG decreased by a mean of -22.3%. Median TG at baseline and M3 was 1.02g/L (0.38-4.18) and 0.8g/L (0.41-3.83) (p=0.0003). Only 2 pts (8%) had high TG at M3. No further significant change was observed beyond M3 with median TC, LDL-C, HDL-C and TG at M12 of 2.2g/L (1.15-2.9), 1.3g/L (0.69-1.84), 0.52g/L (0.38-1.27) and 0.83g/L (0.37-1.61), respectively. Finally, 1 pt developed type 2 DM at M12.Three pts (12%) required statins during the first year of nilotinib therapy: 2 pts with a moderate CVD risk at baseline and in whom LDL-C rose above 1.9g/L and 1 pt with a moderate CVD risk at baseline who developed peripheral artery disease (PAD) at M12, leading to nilotinib discontinuation. By M12, the CVD risk changed from low to high in 1 pt due do to the onset of DM and from moderate to very high in the pt with PAD. ConclusionsNilotinib is associated with a significant and early increase in TC, LDL-C and HDL-C. In contrast, a decrease in TG occurs but this may be due to lifestyle medical advice given to our patients. All patients considered for nilotinib therapy should have an evaluation of blood lipids at baseline and early after the start of therapy. Requirement for lifestyle modifications and lipid lowering treatment by statins should be determined at baseline and throughout therapy according to TC, LDL-C and CVD risk category. The role of nilotinib-induced high LDL-C in the onset of AOD needs to be investigated. Disclosures:Rea:Novartis: Honoraria; BMS: Honoraria; Teva: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Gautier:Novartis: Honoraria. Messas:Novartis: Honoraria. Dombret:Novartis: Research Funding.

AUC Versus Peak–Trough Dosing of Vancomycin

To compare and contrast the pharmacokinetic/pharmacodynamic foundations of traditional "peak-trough" vancomycin dosing methods versus newer "area under the curve" (AUC) strategies. To propose a new AUC-based dosing chart for empirically determining an initial vancomycin dosing regimen designed to achieve a desired AUC24 using the minimum inhibitory concentration (MIC), creatinine clearance (CrCl), and vancomycin clearance (ClVanco). Peak-trough vancomycin dosing is designed to achieve a Cpeak of 20-40 mg/L and a Ctrough of 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. New treatment guidelines for vancomycin suggest that therapy should achieve an AUC24/MIC of ≥400. AUC-based vancomycin dosing derives the daily dose from ClVanco, MIC, and the desired AUC24/MIC, without consideration of the patient's weight. A vancomycin dosing chart is proposed that estimates ClVanco using the following formula developed by Matzke et al: ClVanco in L/h = [(CrClmL/min × 0.689) + 3.66] × 0.06, which simplifies to (CrClmL/min × 0.41) + 0.22. Two levels of dosing are included-high dose (Ctrough: 15-20 mg/L) and moderate dose (Ctrough: 10-15 mg/L). Although the chart has not been validated clinically, it represents the product of standard dosing equations that are used to determine a starting dosing regimen based on well-established vancomycin pharmacokinetic parameters. An understanding of pharmacokinetic and pharmacodynamic principles, including the relevance of AUC in relation to MIC, enables clinicians to make the best use of vancomycin dosing options. The proposed dosing chart is pharmacokinetically valid but has yet to be applied clinically. It provides a foundation for further study of how clinicians can determine an optimal AUC-based starting vancomycin dosing regimen without having to derive ClVanco or AUC24.

A Predictive Pharmacokinetic/Pharmacodynamic Model of Fentanyl for Analgesia/Sedation in Neonates Based on a Semi-Physiologic Approach

Fentanyl is a synthetic opioid commonly used as an anesthetic and also increasingly popular as a sedative agent in neonates. Initial dosage regimens in this population are often empirically derived from adults on a body weight basis. However, ontogenic maturation processes related to drug disposition are not necessarily always body weight correlates. We developed a predictive pharmacokinetic/pharmacodynamic model that includes growth and maturation physiologic changes for fentanyl in neonatal care. Key pharmacokinetic variables and principles (protein binding, clearance, distribution) as related to fentanyl pharmacokinetic/pharmacodynamic behavior in adults (tricompartmental model) and to neonatal physiologic data (organ weights and blood flows, body composition, renal and hepatic function, etc.) were used to guide the building of a semi-physiologic ontogenic model. The model applies to a normal-term neonate without any other intervention. Then, extension to a pharmacokinetic/pharmacodynamic link model for fentanyl was made. The final model was evaluated by predicting the time course of plasma concentrations and the effect of a standard regimen of 10.5 μg/kg over a 1-h period followed by 1.5 μg/kg/h for 48 h. Hepatic clearance was linked to ontogeny of unbound fraction and of α1-acid glycoprotein. All parameters were reduced in the neonate compared to adults but in a differing proportion due to qualitative changes in physiology that are analyzed and accounted for. Systemic clearance (CLS), volume of the central compartment (V1) and steady-state volume of distribution predicted by the model were 0.028 L/min, 1.26 L, and 22.04 L, respectively. Weight-corrected parameters generally decreased in adults compared with neonates, but differentially, e.g., CLS = 0.0093 versus 0.0088 L/min/kg, while V1 = 0.42 versus 0.18 L/kg (neonates vs. adults). Under such complexity a pharmacokinetic/pharmacodynamic model is the appropriate method for rational efficacy targeting. Fentanyl pharmacodynamics in neonates were considered to be similar to those in adults except for the equilibrium rate constant, which was also scaled on an ontogenic basis. The model adequately predicted the reported mean expected concentration-time profiles for the standard regimen. Integrated pharmacokinetic/pharmacodynamic modeling showed that the usually prescribed dosage regimens of fentanyl in neonates may not always provide the optimum degree of sedation. The model could be used in optimal design of clinical trials for this vulnerable population. Prospective clinical testing is the reasonable next step.

Initial dosage regimens of vancomycin for Chinese adult patients based on population pharmacokinetic analysis

To build a population pharmacokinetic model for Chinese adult patients and develop initial dosage regimens for patients with different degrees of renal function to achieve target steady-state trough concentrations in the range of 10 - 15 and 15 - 20 mg/l. Data on serum vancomycin concentration was collected from a retrospective study including 72 Chinese adult patients. NONMEM was used to build the population pharmacokinetic model, and a one-compartment model was chosen to describe the vancomycin concentration-time profile. Internal evaluation by bootstrap and visual predictive check (VPC) was performed to evaluate the robustness and prediction of the final model. Monte Carlo simulations were conducted to develop initial dosage regimens to achieve target trough concentrations. A one-compartment model was built with creatinine clearance (CLcr) as the key covariate influencing drug clearance. The estimated drug clearance for patients with normal renal function (CLcr ≥ 80 ml/min) was 4.90 l/h, and 0.0654 × CLcr if CLcr was < 80 ml/min. The apparent volume of the central compartment was 47.76 l and no covariate was found to affect it. The results of bootstrap analysis were in agreement with the original parameters of the final model, and VPC of the final model demonstrated good predictability. Initial dosage regimens were developed based on the simulations of the population pharmacokinetic model. A one-compartment model fitted the retrospective data and CLcr had a significant effect on drug clearance. Initial dosage regimens for vancomycin were proposed to provide some help to individual therapy for Chinese adult patients with different renal functions.

Amikacin Population Pharmacokinetics in Critically Ill Kuwaiti Patients

Amikacin pharmacokinetic data in Kuwaiti (Arab) intensive care unit (ICU) patients are lacking. Fairly sparse serum amikacin peak and trough concentrations data were obtained from adult Kuwaiti ICU patients. The data were analysed using a nonparametric adaptive grid (NPAG) maximum likelihood algorithm. The estimations of the developed model were assessed using mean error (ME) as a measure of bias and mean squared error (MSE) as a measure of precision. A total of 331 serum amikacin concentrations were obtained from 56 patients. The mean (±SD) model parameter values found were V c = 0.2302 ± 0.0866 L/kg, k slope = 0.004045 ± 0.00705 min per unit of creatinine clearance, k 12 = 2.2121 ± 5.506 h−1, and k 21 = 1.431 ± 2.796 h−1. The serum concentration data were estimated with little bias (ME = −0.88) and good precision (MSE = 13.08). The present study suggests that amikacin pharmacokinetics in adult Kuwaiti ICU patients are generally rather similar to those found in other patients. This population model would provide useful guidance in developing initial amikacin dosage regimens for such patients, especially using multiple model (MM) dosage design, followed by appropriate Bayesian adaptive control, to optimize amikacin dosage regimens for each individual patient.

2262 PERSONALIZED INITIAL DOSE OF TACROLIMUS BASED ON THE CYP3A5 POLYMORPHISM AND ITS IMPACT ON THE 1-MONTH GRAFT FUNCTION: A PRELIMINARY EXPERIENCE

INTRODUCTION AND OBJECTIVES: Patients with CYP3A5*1 allele (CYP3A5 expressers) require a higher daily tacrolimus dose than those with CYP3A5*3/*3 genotype (non-expressers) in order to maintain target trough levels (C0) (Tsuchiya, Transplantation, 2004). Recently, we reported that renal cortical interstitial fibrosis (IF) from 0-hour to 1-year post-transplantation increased in non-expressers than CYP3A5 expressers. Unexpected highly tacrolimus levels in non-expressers might influence the development of IF, despite therapeutic drug monitoring (Miura, Transplantation 2011). Therefore, since January 2011, we have started to a personalized initial dosing regimen of controlled-release tacrolimus based on the CYP3A5 polymorphism. The present study investigated the impact of personalized regimen of tacrolimus on the pharmacokinetics and 1-month graft function comparing to the non-personalized regimen. METHODS: Initial oral doses of tacrolimus were 0.20mg/kg for CYP3A5 expressers and 0.10mg/kg for non-expressers. In the nonpersonalized regimen, all patients received 0.20mg/kg of tacrolimus. The target trough levels of tacrolimus were same between the two regimes. RESULTS: Twenty patients were involved in the personalized regimen; CYP3A5 expressers in 6 and non-expressers in 14 cases. Twenty-five patients were in involved in the non-personalized regimen; CYP3A5 expressers in 10 and non-expressers in 15 cases. In the non-personalized regimen, C0 and area under the blood concentrationtime curve (AUC) of tacrolimus and estimated glomerular filtration rate (eGFR) in CYP3A5 expressers and non-expressers were: C0 (4.8 vs. 8.5 ng/ml, p 0.001) and AUC (218 vs. 373 nghr/ml, p 0.001) at day 1 after first administration of tacrolimus, C0 (5.4 vs 7.8 ng/ml, p 0.004) and AUC (218 vs 287 nghr/ml, p 0.013) and eGFR (59.2 vs 42.4 ml/min/1.73m2, p 0.028) at day 28 post-transplantation. In the personalized regimen, C0 and AUC of tacrolimus and eGFR in CYP3A5 expressers and non-expressers were; C0 (6.9 vs 2.7 ng/ml, p 0.279) and AUC (377 vs 136 nghr/ml, p 0.268) at day 1, C0 (8.9 vs 5.2 ng/mL, p 0.0270) and AUC (332 vs 226 nghr/mL, p 0.073) and eGFR (47.7 vs 64.6 ml/min/1.73m2, p 0.202) at day 28. CONCLUSIONS: The personalized medicine of tacrolimus based on the CYP3A5 polymorphism may decrease the pharmacokinetic difference between CYP3A5 expressers and non-expressers, and it may contribute better graft function in non-expressers in the early post-transplantation.

Phase II study of gemcitabine, cisplatin, and sunitinib (S) in patients with advanced urothelial carcinoma (UC).

282 Background: Sunitinib (S) has single-agent activity in patients with advanced urothelial carcinoma (UC). Preclinical studies in UC demonstrate at least additive antitumor activity combining S with gemcitabine (G) or cisplatin (C). Methods: Patients with chemonaïve metastatic UC were enrolled in a multicenter phase II trial with overall response rate (ORR) as the primary endpoint. The initial dosing regimen, based on a phase I trial (Reck, 2010), was G 1000 mg/m2 IV (Days 1 &amp; 8), C 70 mg/m2 IV (Day 1), and S 37.5 mg PO daily (Days 1-14)/each 21-day cycle (up to 6 cycles), followed by S 37.5 mg daily until progression. Results: From December 2008 to August 2009, 15 eligible patients enrolled. Seven of 15 patients discontinued treatment early (median: 3 cycles) due to toxicity, most often due to recurrent neutropenia and thrombocytopenia. Intrapatient dose reductions were required for G (12/15), C (8/15), and S (10/15). Eight of 15 patients experienced serious adverse events. Based on the toxicity profile, enrollment was held and the dosing regimen was revised to G 800 mg/m2 IV (Days 1 and 8), C 60 mg/m2 IV (Day 1), S 37.5 mg PO daily (Days 1-14). From December 2009 to April 2011, 18 additional patients were enrolled. Despite the reduced starting doses, intrapatient dose reductions were required for G (13/18), C (9/18), and S (15/18). The most frequent Grade 3-4 toxicities for both groups were neutropenia (70%), thrombocytopenia (58%), and anemia (30%). Antitumor activity is shown in the Table. Median PFS was 7.9 and median OS was 13.8 months. Conclusions: Combination G+C+S is poorly tolerated and results in activity comparable to historical results with G+C alone. Supported in part by a grant from Pfizer Inc. [Table: see text]

Selection of the Initial Methadone Regimen for the Management of Iatrogenic Opioid Abstinence Syndrome in Critically Ill Children

Iatrogenic opioid abstinence syndrome (IOAS) is a common complication in critically ill infants and children receiving prolonged exposure to continuous infusions of opioids. Although no guidelines are available regarding management of IOAS in children, several treatment options are available, including clonidine, morphine, and methadone. Methadone is commonly prescribed due to its long half-life and antagonism of the N-methyl-d-aspartate receptor. Different approaches, such as weight-based and formula-based methods, have been used to determine the initial methadone dosing regimen. Because of the vast differences in the recommended dosing regimen from these sources, we conducted a literature search to identify articles evaluating the initial methadone dosing regimen for prevention and/or treatment of IOAS in children. Specifically, we evaluated the reported frequency of withdrawal and oversedation after initiation of methadone treatment. Our literature search was limited to English-language articles in the MEDLINE (1950-March 2011), EMBASE (1988-March 2011), International Pharmaceutical Abstracts (1970-March 2011), and Cochrane Library (1996-March 2011) databases. Relevant abstracts and reference citations were also reviewed. A total of eight reports representing 183 patients were included in the analysis. There was wide discrepancy in the initial methadone dosing regimen. Approximately one-third of all patients experienced withdrawal after starting methadone, and there did not appear to be a difference between weight-based and formula-based regimens. Seven patients experienced oversedation; however, not all articles reported this complication. It appears that a standard approach to initial methadone dosing does not exist because withdrawal occurred despite the regimen started. Therefore, it seems best to begin with the lowest dose possible and titrate to the child's response to avoid complications such as oversedation. Routine monitoring should be performed in all patients to guide clinicians in the management of IOAS.