Therapeutic Drug Monitoring Results Research Articles

A LC/MS/MS micro-method for human plasma quantification of vemurafenib. Application to treated melanoma patients

As previously shown for imatinib, therapeutic drug monitoring (TDM) of vemurafenib should be important to measure efficacy of the treatment in melanoma patient. A micro-method based on liquid chromatography coupled to triple quadrupole spectrometry detection using only 10μL of plasma was validated. A simple protein precipitation with water/acetonitrile was used after addition of vemurafenib-13C6 as internal standard. The ion transitions used to monitor analytes were m/z 490.2→m/z 255.2 and m/z 383.3 for vemurafenib and m/z 496.2→m/z 261.2 and m/z 389.3 for vemurafenib-13C6. Calibration curves were linear in the 0.1–100μg/mL range, the limits of detection and quantification being 0.01μg/mL and 0.1μg/mL, respectively. The intra- and inter-assay precisions evaluated at 0.1, 0.3, 15, 45 and 80μg/mL were lower than 13.3% and the accuracies were in the 93.7–105.8 range. No matrix effect was observed. At steady state, the results of TDM of vemurafenib in 26 patients treated by 960mg twice daily (n=60 samples), 13 patients with 740mg twice daily (n=13) and one with 1200mg twice daily (n=3) showed a great variability of the pharmacokinetics of this compound.

Correlation Between Mycophenolic Acid Blood Level and Renal Dysfunction in Stable Liver Transplant Recipients Receiving Mycophenolate Monotherapy

PurposeMycophenolate mofetil (MMF) is frequently used after liver transplantation (OLT). Mycophenolic acid (MPA) metabolites are eliminated primarily via the kidneys. If renal function declines, clearance is significantly impaired. The aim of this study was to reveal the renal function-dependent changes of MPA level in stable adult OLT recipients receiving MMF monotherapy. MethodsSixty-five OLT recipients were selected from our OLT database of >3500 cases. All had undergone MMF monotherapy with a daily MMF dose of 1000 mg or 1500 mg for more than 2 years, primarily because they could not tolerate calcineurin inhibitors. Their clinical profiles, including MPA therapeutic drug monitoring (TDM) and renal function, were analyzed as a cross-sectional study. ResultsFor the group treated with 1000 mg MMF (n = 40), the 12-hour MPA trough level was 1.20 ± 0.35 μg/mL with serum creatinine (Cr) level ≤1.4 mg/dL in 13 patients; it was 2.78 ± 1.19 μg/mL with Cr >1.4 mg/dL in 16 patients not undergoing hemodialysis and 3.83 ± 0.87 μg/mL in 11 patients undergoing hemodialysis (P < .001). For the group treated with 1500 mg MMF (n = 25), the MPA trough level was 2.23 ± 0.99 μg/mL with Cr ≤1.4 mg/dL in 6 patients; it was 2.81 ± 0.99 μg/mL with Cr >1.4 mg/dL in 18 patients not undergoing hemodialysis and 3.5 μg/mL in 1 patient undergoing hemodialysis (P = .21). ConclusionsConsidering the potential therapeutic range of MPA, the suggested MMF dosage for Korean adult OLT recipients requiring hemodialysis may be set around 1000 mg per day. We suggest adjusting the MMF dosage on an individualized basis according to the results of MPA TDM, particularly for patients with markedly impaired renal function.

What, if all alerts were specific – Estimating the potential impact on drug interaction alert burden

PurposeClinical decision support systems (CDSS) may potentially improve prescribing quality, but are subject to poor user acceptance. Reasons for alert overriding have been identified and counterstrategies have been suggested; however, poor alert specificity, a prominent reason of alert overriding, has not been well addressed. This paper aims at structuring modulators that determine alert specificity and estimating their quantitative impact on alert burden. MethodsWe developed and summarized optimizing strategies to guarantee the specificity of alerts and applied them to a set of 100 critical and frequent drug interaction (DDI) alerts. Hence, DDI alerts were classified as dynamic, i.e. potentially sensitive to prescription-, co-medication-, or patient-related factors that would change alert severity or render the alert inappropriate compared to static, i.e. always applicable alerts not modulated by cofactors. ResultsWithin the subset of 100 critical DDI alerts, only 10 alerts were considered as static and for 7 alerts, relevant factors are not generally available in today's patient charts or their consideration would not impact alert severity. The vast majority, i.e. 83 alerts, might require a decrease in alert severity due to factors related to the prescription (N=13), the co-medication (N=11), individual patient data (N=36), or combinations of them (N=23). Patient-related factors consisted mainly of three lab values, i.e. renal function, potassium, and therapeutic drug monitoring results. ConclusionThis paper outlines how promising the refinement of knowledge bases is in order to increase specificity and decrease alert burden and suggests how to structure knowledge bases to refine DDI alerting.

Therapeutic drug monitoring in the treatment of tuberculosis: a retrospective analysis

Tuberculosis (TB) in-patient treatment unit in Vancouver, Canada. To examine the results of therapeutic drug monitoring (TDM) in anti-tuberculosis treatment. We performed a retrospective analysis of TDM data from 2000 to 2010. All in-patients treated for TB with TDM performed during their treatment course were included. TDM was performed on 52 patients in 76 treatment episodes from 2000 to 2010. Overall, 103/213 (48.4%) drug levels measured were low, and 5/213 (2.3%) were high. At least one drug level was low in 47/52 (90.3%) patients. Initial serum levels were low in respectively 76.6% and 68.4% of isoniazid (INH) and rifampicin (RMP) levels. In contrast, only 2.9% of initial pyrazinamide levels were low. Five patients with a susceptible strain on initial presentation later developed drug-resistant disease, with all five patients demonstrating at least one low drug level and two demonstrating multiple low levels. Dose adjustments were made in response to 26 INH and RMP levels, with variable serum responses. In this population with high rates of treatment failure and acquired resistance, we demonstrate that most patients had low drug levels. Prospective studies are required to examine the relationship between drug levels and clinical outcomes.

Evaluating Appropriateness of Digoxin, Carbamazepine, Valproic Acid, and Phenytoin Usage by Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) is a useful tool for the optimization of drug therapy. The aim of this retrospective study was to evaluate the appropriateness of carbamazepine, phenytoin, valproic acid, and digoxin therapy by using TDM data. We evaluated the appropriateness of drug usage in 325 patients who received carbamazepine, valproic acid, phenytoin, or digoxin in a large teaching hospital during the period from March 2010 to January 2011. The serum drug levels were measured by cloned enzyme donor immunoassay (CEDIA). A total of 325 TDM tests were performed in this period. In our TDM unit, valproic acid was the most evaluated test among the samples obtained. In 100 valproic acid-treated patients, serum levels in 58 patients (58%) were within the therapeutic range. While 11 patients (11%) had serum levels in the above-therapeutic range, 31 patients (31%) had sub-therapeutic levels of valproic acid: The results of TDM were mostly found in the therapeutic range for carbamazepine. A total of 91 request forms were collected. The overall data show that 64 patients (70.3%) had serum carbamazepine levels within the therapeutic range. In the phenytoin assays, the mean plasma concentrations generally did not reach the therapeutic range. Among the total of 49 blood samples, the highest number of sub-therapeutic levels (65.3%) were detected for phenytoin. Similarly, inappropriate levels of digoxin were established in about half of all cases. This study gives information about the inappropriate usage of digoxin and phenytoin in respect to the results of our TDM practice. Our results suggest that there is a need for interventions to improve the appropriate use of digoxin and phenytoin in patients treated with these drugs.

How well does self-reported adherence fare compared to therapeutic drug monitoring in HAART?

ObjectiveThe aim of the study was to determine how well self-reported adherence fares compared to therapeutic drug monitoring in monitoring HAART adherence. MethodsWe administered a validated self-reported adherence (SRA) questionnaire to 925 HIV patients on HAART in a large Malaysian hospital from 2010 to 11. We also performed Therapeutic Drug monitoring (TDM) by concurrently collecting and testing blood samples for Efavirenz, Nevirapine and Lamivudine using Liquid Chromatography/Mass Spectrometry. We compared the SRA against the TDM results. Sensitivity, specificity, positive (PPV) and negative predictive (NPV) and diagnostic accuracy values were computed for each drug. ResultsSelf-reported adherence (SRA) over-estimates adherence by between 6 and 10percentage points compared to therapeutic drug monitoring (TDM). SRA is highly sensitive with sensitivity exceeding 0.90 but is not very specific (0.56–0.63). PPV for SRA ranged between 0.76 (Lamivudine) and 0.84 (Efavirenz) while NPV ranged between 0.78 (Lamivudine) and 0.81 (Efavirenz). Overall diagnostic accuracy ranged between 0.76 (Lamivudine) and 0.84 (Nevirapine). ConclusionSelf-reported adherence is a surprisingly accurate instrument for measuring HAART adherence compared to TDM and can be reliably used in practice in resource-poor settings.

Application of Beta-lactam Therapeutic Drug Monitoring in Clinical Practice Using HPLC

In beta-lactam therapy, investigation of the pharmacokinetic-pharmacodynamic (PK-PD) relationship has provided surrogate makers to predict clinical outcome. This study was designed to verify the therapeutic efficacy and clinical utility of beta-lactam therapeutic drug monitoring (TDM) in critically ill patients using high-performance liquid chromatography (HPLC). This cohort study included 13 patients who were intravenously administered ceftazidime (n = 6), cefepime (n = 1), imipenem (n = 1), meropenem (n = 1), or piperacillin (n = 4). Blood samples were collected at 3 time points fitted to a 1-compartment model, and concentrations were determined using HPLC. The PK-PD target was the percentage of the dosing interval during which the antibiotic concentration exceeded the minimum inhibitory concentration for the pathogens (%T > MIC), which is 50% for penicillins (piperacillin), 60% for cephalosporins (ceftazidime and cefepime), and 40% for carbapenems (imipenem and meropenem). Our process using HPLC enables the analytical results of TDM to be available within half a day. The results revealed significant inter-patient pharmacokinetic variability. During the initial regimen, beta-lactam concentrations reached the target %T > MIC in all patients, and dosage reduction was required for 5 patients (38%). Of the 13 evaluable patients, clinical improvement was observed in 11 (85%), and microbiological success was observed in 10 (77%). In summary, beta-lactam TDM achieved the treatment goals and might also allow for the personalization to prevent overdosing for variable pharmacokinetic changes in critically ill patients. These findings indicate that beta-lactam TDM using HPLC can be used in the standard pharmacy clinical practice for critically ill patients.

Positive Bias in Mycophenolic Acid Concentrations Determined by the CEDIA Assay Compared to HPLC‐UV Method: Is CEDIA Assay Suitable for Therapeutic Drug Monitoring of Mycophenolic Acid?

Both immunoassays and chromatographic methods are available for therapeutic drug monitoring of mycophenolic acid (MPA), an immunosuppressant. We studied the suitability of cloned enzyme donor immunoassay (CEDIA) assay for routine monitoring of MPA by comparing values obtained by the CEDIA assay with corresponding values obtained by using a high-performance liquid chromatography combined with ultraviolet detection (HPLC-UV) method. We compared MPA concentrations obtained by a reference HPLC-UV method and CEDIA assay on Hitachi 917 analyzer (Roche Diagnostics, Indianapolis, IN) using 60 patient specimens (18 liver transplant recipient and 42 kidney transplant recipients). When MPA concentrations in all 60 transplant recipients obtained by the HPLC-UV (x-axis) method were compared with corresponding values obtained by the CEDIA method (y-axis), the following regression equation was obtained: y = 1.1558x + 0.2876 (r = 0.97). Interestingly, much lower bias was observed in 42 renal transplant recipients as revealed by the following regression equation; y = 1.1181x + 0.2745 (r = 0.98). However, more significant positive bias was observed in 18 liver transplant recipients as following regression equation as observed: y = 1.3337x + 0.1493 (r = 0.94). We conclude that MPA concentrations determined by the CEDIA assay showed significant positive bias compared to HPLC-UV method. Therefore, caution must be exercised in interpreting therapeutic drug monitoring result of MPA if CEDIA assay is used.

Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring

ObjectiveBecause pharmacokinetic data are limited, continuous infusions of vancomycin in neonates are administered using different dosing regimens. The aim of this work was to evaluate the results of vancomycin therapeutic...

A Validated HPLC Method for the Monitoring of Thiopurine Metabolites in Whole Blood in Paediatric Patients with Inflammatory Bowel Disease

Therapeutic drug monitoring (TDM) of major metabolites of thiopurine drugs is a widely used tool for assessing treatment efficacy and toxicity in patients with inflammatory bowel disease (IBD). We report the laboratory and clinical validation of a simple and reliable high performance liquid chromatography (HPLC) method for the measurement of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) on paediatric patients with IBD. The aim of this paper is to develop and validate a method for the measurement of 6-TGN and 6-MMP applicable to routine practice and to evaluate the usefulness of the TDM of thiopurine drugs in children with IBD attending our Gastroenterology Unit. The HPLC method was validated following international guidelines starting from red blood cells (RBC) and whole blood (WB). A comparison between RBC and WB was assessed. The usefulness of TDM was then evaluated using the new method from WB in 47 paediatric patients with IBD treated with thiopurine drugs. WB and RBC resulted in interchangeable matrices. The majority of patients had the metabolite levels inside the therapeutic ranges. A moderate correlation was found between 6-MMP concentration and the dose of thiopurines. A higher percentage of non responders was found among patients with lower levels of 6-TGN. Toxicity was found in eight patients and was evaluated in respect to the metabolite concentration. The described HPLC method is applicable to routine practice and it is suitable for its use in multicentric studies. Our results of TDM on paediatric IBD patients can contribute to clarify its role in their therapeutic management.

Use of therapeutic drug monitoring to treat Elizabethkingia meningoseptica meningitis and bacteraemia in an adult

Use of therapeutic drug monitoring to treat Elizabethkingia meningoseptica meningitis and bacteraemia in an adult

The Concentration of Cyclosporine Metabolites Is Significantly Lower in Kidney Transplant Recipients With Diabetes Mellitus

Diabetes mellitus is prevalent among kidney transplant recipients. The activity of drug metabolizing enzymes or transporters may be altered by diabetes leading to changes in the concentration of parent drug or metabolites. This study was aimed to characterize the effect of diabetes on the concentration of cyclosporine (CsA) and metabolites. Concentration-time profiles of CsA and metabolites (AM1, AM9, AM4N, AM1c, AM19, and AM1c9) were characterized over a 12-hour dosing interval in 10 nondiabetic and 7 diabetic stable kidney transplant recipients. All patients were male, had nonfunctional CYP3A5*3 genotype, and were on combination therapy with ketoconazole. The average daily dose (±SD) of CsA was 65 ± 21 and 68 ± 35 mg in nondiabetic and diabetic subjects, respectively (P = 0.550). Cyclosporine metabolites that involved amino acid 1 (AM1, AM19, AM1c) exhibited significantly lower dose-normalized values of area under the concentration-time curve in patients with diabetes. Moreover, during the postabsorption phase (≥3 hours after dose), metabolite-parent concentration ratios for all metabolites, except AM4N, was significantly lower in diabetic patients. The pharmacokinetic parameters of ketoconazole were similar between the 2 groups thus excluding inconsistent ketoconazole exposure as a source of altered CsA metabolism. This study indicates that diabetes mellitus significantly affects the concentration of CsA metabolites. Because CsA is eliminated as metabolites via the biliary route, the decrease in the blood concentration of CsA metabolites during postabsorption phase would probably reflect lower hepatic cytochrome P450 3A4 enzyme activity. However, other mechanisms including altered expression of transporters may also play a role. Results of cyclosporine therapeutic drug monitoring in diabetic patients must be interpreted with caution when nonspecific assays are used.

Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome

To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting. Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity. A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8–60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution). We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.

Therapeutic Drug Monitoring in De Novo Kidney Transplant Receiving the Modified-Release Once-Daily Tacrolimus

Introduction Advagraf (AVF) a new formulation of tacrolimus (TRL), allows once-daily administration while showing similar efficacy and safety to the conventional Prograf (PGF), which is prescribed twice daily. Our study sought to compare short-term therapeutic drug monitoring (TDM) of AVF and PGF in de novo kidney transplants. Patients and Methods We retrospectively collected results of TDM performed on blood trough samples (C0) using an LC- MS/MS assay to quantify TRL exposure in the two groups. Twelve subjects received initial immunosuppression with AVF associated with mycophenolic acid, steroids, and immunoglobulins. We compared median doses and C0 levels with those obtained in 18 cases receiving an equivalent dose of PGF during the same period. Results and Discussion Although both groups showed similar mean C0, the median dose in the AVF group tended to be higher than the PGF group—respectively, 9.8 and 7.9 mg/d—which may be attributed to the once-daily regimen, which inevitably results in lower C0 levels compared to the twice-a-day regimen, while overall exposure appeared similar in terms of area under the curve (AUC). This observation occured especially during the first weeks despite the extended release formulation. In fact, one patient who showed a low C0 (5.9 ng/mL) while receiving high doses of AVF (0.28 mg/kg), the AUC of 356 and 211 ng.h/mL performed on days 12 and 18 respectively showed exposure consistent with efficacy. Conclusion In conclusion, it seemed to be necessary to use higher doses (25%) of Advagraf to reach the targeted C0 levels during the first weeks posttransplant. For patients who do not reach the targeted C0 despite high doses, TRL exposure should be assessed by AUC or peak levels (C4h).

Utility of therapeutic drug monitoring in the management of HIV-infected pregnant women in receipt of lopinavir

The pharmacokinetics of antiretroviral drugs in pregnancy is poorly understood. We reviewed the use of therapeutic drug monitoring (TDM) in clinical settings to document plasma concentrations of lopinavir during pregnancy and investigated how clinicians acted upon TDM results. A retrospective review was carried out of all HIV-infected pregnant women taking boosted lopinavir-based highly active antiretroviral therapy (HAART) at five National Health Service (NHS) centres in the UK between May 2004 and March 2007. Seventy-three women in receipt of lopinavir were identified, of whom 89% had plasma lopinavir concentrations above the suggested minimum recommended for wild-type HIV. Initial TDM results prompted dosage change in 10% and assessment of adherence and/or pharmacist review in 11%. TDM was repeated in 29%. TDM can play an important role in the clinical management of HIV-positive pregnant women, allowing informed dose modification and an alternative measure of adherence.

Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry

Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time <3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in patient samples, but not in spiked calibrator samples. Comparison with LC-MS/MS disclosed a significant bias with higher concentrations measured by LC-MS/MS, while UPLC-MS/MS showed excellent agreement with the commercially available HPLC method. In the LC-MS/MS procedure, comparably wide and left side shifted peaks were noticed. This could be ascribed to in-source fragmentation of conjugate metabolites during electrospray ionisation. Precursor and product ion scans confirmed the assumption that the additional compounds are posaconazole glucuronides. Reducing the cone voltage led to disappearance of the glucuronide peaks. Slight modification of the LC-MS/MS method enabled separation of the main interference, leading to significantly reduced deviation. These results highlight the necessity to reliably eliminate interference from labile drug metabolites for correct TDM results, either by sufficient separation or selective MS conditions. The presented UPLC-MS/MS method provides a reliable and fast assay for TDM of posaconazole.

Drug-Drug Interaction Between Itraconazole and the Protease Inhibitor Lopinavir/Ritonavir

To report the results of therapeutic drug monitoring of lopinavir/ritonavir and itraconazole concentrations in an HIV-infected male who was treated for histoplasmosis. A 34-year-old HIV-infected man who had recently initiated efavirenz-based antiretroviral therapy was diagnosed with disseminated Histoplasma capsulatum infection. In the hospital, lopinavir/ritonavir 400 mg/100 mg twice daily replaced efavirenz to avoid efavirenz-itraconazole interactions. After 14 days of liposomal amphotericin B therapy, itraconazole solution was initiated at 150 mg twice daily for 3 days, followed by 200 mg daily. Prior to itraconazole initiation, lopinavir trough concentration was 7.4 mg/L. The lopinavir trough concentration 15 days later, after 14 days of itraconazole, was 6.8 mg/L. An itraconazole concentration measured 2 hours post-dose on day 15 of oral therapy was 1.9 microg/mL. After 2 weeks of liposomal amphotericin, urine Histoplasma antigen was 27.23 ng/mL; after 5 months of oral itraconazole therapy, it decreased to 5.24 ng/mL. Plasma HIV RNA decreased 4.26 log(10) in 5 months to less than 40 copies/mL. The patient has demonstrated marked clinical improvement. In this case, dosing recommendations of itraconazole 200 mg daily with lopinavir/ritonavir were appropriate. Lopinavir trough concentrations were not significantly different following the addition of itraconazole and were above the minimum target of 1 mg/L in treatment-naïve patients. The itraconazole concentration was above the recommended concentration of at least 1 microg/mL. The dose of itraconazole was reduced to 200 mg daily as recommended by current guidelines, and therapeutic drug monitoring of both itraconazole and lopinavir concentrations confirmed that no further dosage adjustments were necessary.

Factors influencing pharmacokinetics of prophylactic posaconazole in patients undergoing allogeneic stem cell transplantation.

The objectives of the present study were to elucidate the factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic hematopoietic stem cell transplant (SCT) recipients. Between May 2007 and November 2008, clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75.8 liters/h (95% confidence interval [CI], 65.2 to 86.4 liters/h) and the apparent volume being distribution of 835 liters (95% CI, 559 to 1,111 liters). Among the covariates tested, significant effects were found for age (decrease in the volume of distribution of 123 liters per year of age) and the presence of diarrhea (59% loss of bioavailability). A basis for prediction of the mean posaconazole concentrations in allogeneic SCT recipients with hematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to the presence of diarrhea and according to age appear to be justified before TDM results are available.

Safety and efficacy of a double-boosted protease inhibitor combination, saquinavir and lopinavir/ ritonavir, in pretreated children at 96 weeks

This study aimed to assess the long-term efficacy, safety and use of therapeutic drug monitoring (TDM) of a double-boosted protease inhibitor (PI) combination, saquinavir (SQV) and lopinavir/ritonavir (LPV/r), in Thai HIV type-1 (HIV-1)-infected children who had failed on reverse transcriptase inhibitors. In total, 50 children from two sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4(+) T-cell count and percentage, viral load (VL; HIV-1 RNA), minimum plasma drug concentrations (C(min)) and drug safety laboratory evaluations were monitored. Virological failure was defined as having two consecutive VL measures >400 copies/ml after week 12. An intention-to-treat analysis was performed. Baseline data were a median age of 9.3 years (interquartile range [IQR] 7.1-11.2), VL 4.8 log(10) copies/ml (IQR 4.5-5.1) and CD4(+) T-cell percentage 7% (IQR 3.0-9.5). CDC classifications were N=4%, A=14%, B=68% and C=14% of participants. Median CD4(+) T-cell percentage and CD4(+) T-cell count increase were 14% (IQR 7-19) and 558 cells/mm(3) (IQR 308-782), respectively (both P<0.001). Overall, 37 (74%) children achieved VL<50 copies/ml with significant differences between sites (90% versus 63%). Over 96 weeks, 10 patients had virological failure. Total cholesterol and high-density lipoprotein increased significantly over time, whereas the triglycerides and low-density lipoprotein did not. Approximately 50% of participants reported no change in body shape, and 33%, 43% and 39% reported fatter arms, face and abdomen, respectively. LPV and SQV C(min) were high and stable over time. Double-boosted SQV+LPV/r was an effective and safe alternative for a second-line regimen in children. Hypercholesterolaemia needs close follow-up. On the basis of the TDM results, PI dose reduction in this population should be considered.

Cerebrospinal Fluid Compartmental Pharmacokinetics of Amikacin in Neonates

To describe and investigate the covariate effects of cerebrospinal fluid (CSF) amikacin pharmacokinetics in neonates, CSF samples were prospectively collected from neonates in whom amikacin had been initiated before a diagnostic lumbar puncture was performed. CSF analysis (amikacin concentration, white blood count [WBC], glucose content, and protein concentration) and amikacin therapeutic drug monitoring results (peak and trough concentrations) in serum were recorded. Correlations (Spearman rank) between the CSF amikacin concentration and the CSF WBC and glucose and protein concentration were investigated. There were 44 CSF amikacin concentrations and 83 serum samples available from 43 neonates (mean postmenstrual age, 36 weeks [range, 26 to 41 weeks]; mean weight, 2.43 kg [range, 0.87 to 3.86 kg]). The median time interval between initiation of amikacin administration and CSF sampling was 25 h (range, 2.5 to 93.7 h). The median amikacin concentration in the CSF was 1.08 mg/liter (range, 0.34 to 2.65 mg/liter), and the mean trough and peak amikacin concentrations in serum were 3.8 +/- 2.5 mg/liter and 35.7 +/- 5.9 mg/liter, respectively. A correlation between CSF amikacin and CSF protein contents (P < 0.01, r = 0.41, 95% confidence interval = 0.13 to 0.63) but not between CSF WBC and CSF glucose was documented. A two-compartment (central and CSF) linear disposition model was used to estimate population pharmacokinetics. The half time for equilibration (T(eq)) between serum and CSF compartments was used as a measure of blood-brain barrier permeability. The T(eq) was 7.58 h (coefficient of variation [CV] = 49.1%) with a partition coefficient of 0.103 (CV = 26.4%). There was no relationship between the T(eq) and CSF WBC, CSF glucose content, or CSF protein content.