TRough versus AUC Monitoring of cyclosporine: A randomized comparison of adverse drug reactions in adult allogeneic stem cell recipients (TRAM study).

OBJECTIVE: To investigate the incidence and severity of adverse drug reactions of cyclosporine using AUC-targeted therapeutic drug monitoring (TDM) compared to trough level (Ctrough )-targeted TDM in adult allogeneic stem cell recipients. METHODS: Blind, monocenter, intervention study. Subjects were 1:1 randomized into either an AUC group or a Ctrough group. Adverse drug reactions were accessed two and four weeks after start of treatment. RESULTS: Forty patients were included, resulting in 15 evaluable subjects (AUC group) and 13 evaluable subjects (Ctrough group). Grade two/three toxicity was observed in 46% (Ctrough group) versus 60% of subjects (AUC group) (P = .463). There was no significant difference between two and four weeks after start of cyclosporine for nausea (P = .142 resp. P = .122), renal dysfunction (P = .464 resp. P = 1.000), and hypomagnesemia (P = 1.000 resp. P = .411). Subjects in the AUC group reached the therapeutic goal earlier (72,7% versus 43,0% at third sampling point, P = .332) and were within the target range more consistently. CONCLUSION: This study showed no reduction in incidence and severity of cyclosporine-induced toxicity with AUC- versus trough level-targeted TDM. Although modeled dosing based on AUC led to faster optimal target attainment, this did not result in less toxicity in the early days after transplantation.

Are Dutch dental students and dental-care providers competent prescribers of drugs?

Dental students and dental-care providers should be able to prescribe drugs safely and effectively. As it is unknown whether this is the case, we assessed and compared the prescribing competence of dental students and dental-care providers in the Netherlands. In 2017, all Dutch final-year dental students and a random sample of all qualified general dental practitioners and dental specialists (oral and maxillofacial surgeons and orthodontists) were invited to complete validated prescribing knowledge-assessment and skills-assessment instruments. The knowledge assessment comprised 40 multiple-choice questions covering important drug topics. The skills assessment comprised three common clinical case scenarios. For the knowledge assessment, the response rates were 26 (20%) dental students, 28 (8%) general dental practitioners, and 19 (19%) dental specialists, and for the skills assessment the response rates were 14 (11%) dental students, eight (2%) general dental practitioners, and eight (8%) dental specialists. Dental specialists had higher knowledge scores (78% correct answers) than either dental practitioners (69% correct answers) or dental students (69% correct answers). A substantial proportion of all three groups made inappropriate treatment choices (35%-49%) and prescribing errors (47%-70%). Although there were some differences, dental students and dental-care providers in the Netherlands lack prescribing competence, which is probably because of poor prescribing education during under- and postgraduate dental training. Educational interventions are urgently needed.

Pharmacology of Thiopurine Therapy in Inflammatory Bowel Disease and Complete Blood Cell Count Outcomes: A 5-Year Database Study.

BACKGROUND: Thiopurines are the prerequisite for immunomodulation in inflammatory bowel disease (IBD) therapy. When administered in high (oncological) dose, thiopurine metabolites act as purine antagonists, causing DNA-strand breakage and myelotoxicity. In lower IBD dosages, the mode of action is primarily restricted to anti-inflammatory effects. Then, myelosuppression and hepatotoxicity are the most common adverse events of thiopurines. The aim of this study was to assess the effect of thiopurine metabolites on hematologic and hepatic parameters and to determine which patient characteristics are related to generation of thiopurine metabolites. METHODS: The authors scrutinized the therapeutic drug monitoring database of the VU University medical center and subsequently merged this database with the Clinical Laboratory database of our hospital covering the same time period (2010-2015). RESULTS: The authors included 940 laboratory findings of 424 unique patients in this study. Concentrations of 6-thioguanine nucleotides (6-TGN) correlated negatively with red blood cell count, white blood cell count, and neutrophil count in both azathioprine (AZA) and mercaptopurine users. There was a positive correlation with mean corpuscular volume. In patients using 6-thioguanine, 6-TGN concentrations correlated positively with white blood cell count. Furthermore, there was an inverse correlation between patient's age and 6-TGN concentrations in patients using AZA or 6-thioguanine, and we observed an inverse correlation between body mass index and 6-TGN concentrations in patients using AZA or mercaptopurine. No relations were observed with liver test abnormalities. CONCLUSIONS: Thiopurine derivative therapy influenced bone marrow production and the size of red blood cells. Age and body mass index were important pharmacokinetic factors in the generation of 6-TGN.

Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.

BACKGROUND: The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy. METHODS: Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy. RESULTS: Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01). CONCLUSIONS: This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.

Clinical validation of dried blood spot sampling in therapeutic drug monitoring of ciclosporin A in allogeneic stem cell transplant recipients: direct comparison between capillary and venous sampling.

BACKGROUND: The immunosuppressive drug ciclosporin A has a narrow therapeutic window and a large inter- and intraindividual pharmacokinetic variability. Therapeutic drug monitoring of ciclosporin is usually performed in ethylenediaminetetraacetic acid blood, obtained by venous sampling. Dried blood spot sampling (DBS) could be a useful alternative sampling method, which also easily allows multiple sampling, for example, for obtaining area under the curve. With DBS, capillary blood is obtained from a finger prick with an automatic lancet by the patients themselves, and the drop of blood is applied to sampling paper. This may limit the number and duration of hospital visits for these patients. METHODS: We describe a validation study in which venous and finger prick blood samples were collected at the same time. Venous sampling was performed by venipuncture, and the ethylenediaminetetraacetic acid blood samples were collected and stored at 4°C until analysis. Finger prick blood samples were collected using an automatic lancing device. The volume of the blood drops of patients was approximately 30 µL, and blood spots of about 10-mm diameter were produced. Paper disks with a diameter of 8 mm were punched out with an electromagnetic-driven hole puncher. DBS was compared with the routine assay in venous blood. The study population consisted of adult patients (18 years or older) who were treated with ciclosporin A and routinely monitored for adequate blood concentrations. RESULTS: Thirty-eight duplicate dried blood spots and venous samples were studied. Using weighted Deming regression, the slope was 1.01 with a standard error of 0.03 associated with an intercept of -9.0 (standard error = 5.9). These results indicate that there is no significant difference between the 2 sampling methods. For the medical decision level of 300 mcg/L, the bias was -4.7 mcg/L with a 95% confidence interval of -19.2 to 9.8 mcg/L. The Altman-Bland plot showed no difference between the 2 sampling methods. CONCLUSIONS: Our results demonstrate that DBS is a valid alternative for conventional venous sampling in allogeneic stem cell transplant recipients.

Rapid quantification of gabapentin, pregabalin, and vigabatrin in human serum by ultraperformance liquid chromatography with mass-spectrometric detection.

BACKGROUND: Gabapentin (GBP), pregabalin (PRG), and vigabatrin (VIG) are used for the prevention and treatment of epileptic seizures. The developed method was applied to samples from subjects participating in a pharmacokinetic study of GBP. METHODS: Sample pretreatment consisted of adding 20 µL of trichloroacetic acid (30%; vol/vol) and 200 µL of GBP-d4 in acetonitrile as an internal standard to 20 µL of serum. Chromatographic separation was performed on an Acquity separation module using a Kinetex RP18 column. The aqueous and organic mobile phases were 2 mM ammonium acetate supplemented with 0.1% formic acid in water and acetonitrile, respectively. The detection by a tandem quadrupole mass spectrometer, operating in the positive mode using multiple reaction monitoring, was completed within 2 minutes. RESULTS: The method was linear over the range of 0.03-25 mg/L for GBP, 0.03-25 mg/L for PRG, and 0.06-50 mg/L for VIG. The between- and within-run accuracies ranged from 90% to 107%. The between- and within-run imprecisions of the method were <10%. Stability data show no significant decrease of the analytes. A relative matrix effect of -1%, 0.2%, and -5% was determined for GBP, PRG, and VIG, respectively. CONCLUSIONS: A simple and sensitive ultraperformance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of GBP, PRG, and VIG in human serum. The reported method provided the necessary linearity, precision, and accuracy to allow the determination of GBP, PRG, and VIG for therapeutic drug monitoring and clinical research purposes.

The impact of age on lamotrigine and oxcarbazepine kinetics: a historical cohort study.

Age as well as estrogen levels may have an impact on the pharmacokinetics of lamotrigine (LTG) and monohydroxycarbazepine (MHD), the active metabolite of oxcarbazepine (OXC). To assess the effects of age and menopause, we evaluated retrospectively a therapeutic drug-monitoring database. Samples from 507 women and 302 men taking LTG and 464 women and 319 men taking OXC were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM software and were compared with a population pharmacokinetic model based on samples of 1705 women and 1771 men taking carbamazepine (CBZ). Age was a significant factor contributing to pharmacokinetic variability in individuals using LTG, OXC, and CBZ with increasing clearance as a function of bioavailability (Cl/F) over age 18, a maximum Cl/F at 33years (CBZ) and 36 years (LTG and OXC), and a gradual decrease of Cl/F towards older age. We found no effect of perimenopausal age range on LTG and MHD clearance.

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT). • It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole). • Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS • A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIM To develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODS The pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTS Twenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h(-1) (relative standard deviation [RSD]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V(c) ) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t(lag) ) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3. Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction. CONCLUSIONS The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration-time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.

Comparing cystatin C and creatinine in the diagnosis of pediatric acute renal allograft dysfunction.

BACKGROUND: Allograft function following renal transplantation is commonly monitored using serum creatinine. Multiple cross-sectional studies have shown that serum cystatin C is superior to creatinine for detection of mild to moderate chronic kidney dysfunction. Recent data in adults indicate that cystatin C might also be a more sensitive marker of acute renal dysfunction. This study aims to compare cystatin C and creatinine for detection of acute allograft dysfunction in children using pediatric RIFLE (risk of renal dysfunction, injury to the kidney, failure or loss of kidney function, end stage renal disease) criteria for acute kidney injury. METHODS: Retrospective chart review of post-transplant period in 24 patients in whom creatinine and cystatin C were measured every day. Allograft dysfunction was defined as a sustained rise in marker concentration above the mean of the three preceding measurements. RESULTS: In total, there were 13 episodes of allograft dysfunction. Maximum RIFLE stages with creatinine were 'R' in 7, 'I' in 4, and 'F' in 2, with cystatin C 'R' in 6, 'I' in 4 and 'F' in 3, respectively. In 9/13 cases, both markers rose simultaneously, in three, the rise in creatinine preceded cystatin C by 1-5 days (median 4). In one case, the rise in cystatin C preceded creatinine by 1 day. The time lag was not statistically different. The maximum relative rise of creatinine was significantly higher than cystatin C. By multiple linear regression analysis, the maximum rise of cystatin C was related to the maximum rise of creatinine, but independent of patient age, gender, steroid dose, and anthropometric data. CONCLUSIONS: In this pediatric population, cystatin C was not superior to creatinine for the detection of acute allograft dysfunction.

Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters.

Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3-89.5% versus 76.3-78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.

Validated liquid chromatography-tandem mass spectroscopy method for the simultaneous quantification of four antimycotic agents in human serum.

A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of voriconazole, fluconazole, posaconazole, itraconazole, and hydroxyitraconazole in human serum. A simple protein precipitation was used as sample pretreatment with ketoconazole as the internal standard. Chromatographic separation was performed on a Waters Alliance 2795 liquid chromatography system using a XBridge RP18 column. The mass spectrometer from Micromass was equipped with an electrospray ionization probe operating in the positive mode using multiple reaction monitoring. The method was linear over the range of 0.01 to 5.00 mg/L for itraconazole, 0.01 to 5.00 mg/L for OH-itraconazole, 0.02 to 10.00 mg/L for voriconazole, 0.06 to 30.00 mg/L for fluconazol, and 0.02 to 10.00 mg/L for posaconazole. The between- and within-run accuracy ranged from 92% to 110%. The between- and within-run imprecision of the method was less than 11%. The reported method provided the necessary linearity, precision, and accuracy to allow the determination of four antimycotic agents for therapeutic drug monitoring and pharmacokinetic-pharmacodynamic studies.

Population Pharmacokinetics of Vincristine Related to Infusion Duration and Peripheral Neuropathy in Pediatric Oncology Patients.

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1-5 occasions (1-8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.

Vincristine-induced peripheral neuropathy in children with cancer: A systematic review.

Vincristine-induced peripheral neuropathy (VIPN) is a dose-limiting side effect of vincristine (VCR) treatment in children, leading to diminished quality of life. Much remains unknown about the underlying mechanisms of VIPN. This review systematically summarizes the available literature concerning contributing factors of VIPN development in children. Studied factors include patient characteristics, VCR dose, administration method, pharmacokinetics, and genetic factors. Furthermore, this review reports on currently available tools to assess VIPN in children. In total, twenty-eight publications were included. Results indicate that Caucasian race, higher VCR dose, older age and low clearance negatively influence VIPN, although results regarding the latter two factors were rather conflicting. Moreover, genetic pathways influencing VIPN were identified. Furthermore, the studied tools to assess VIPN seriously impairs comparability across study results. Studying the factors and their interactions that seem to influence VIPN in children, should aid in personalized VCR treatment, thereby increasing VCR effectiveness while minimizing toxicity.

Dried blood spot sampling of nilotinib in patients with chronic myeloid leukaemia: a comparison with venous blood sampling.

OBJECTIVES: To compare nilotinib concentrations obtained by venous blood sampling and dried blood spot (DBS) in patients with chronic myeloid leukaemia (CML). It was investigated how to predict nilotinib plasma levels on the basis of DBS. METHODS: Forty duplicate DBS and venous blood samples were collected from 20 patients. Capillary blood was obtained by finger prick and spotted on DMPK-C Whatman sampling paper, simultaneously with venous blood sampling. Plasma concentrations were predicted from DBS concentrations using three methods: (1) individual and (2) mean haematocrit correction and (3) the bias between plasma and DBS concentrations. Results were compared using Deming regression and Bland-Altman analysis. KEY FINDINGS: Nilotinib plasma concentrations ranged from 376 to 2663 µg/l. DBS concentrations ranged from 144 to 1518 µg/l. The slope was 0.56 (95% CI, 0.51 to 0.61) with an intercept of -41.68 µg/l (95% CI, -93.78 to 10.42). Mean differences between calculated and measured plasma concentrations were -14.3% (method 1), -14.0% (method 2) and -0.6% (method 3); differences were within 20% of the mean in 73%, 85% and 80% of the samples, respectively. The slopes were respectively 0.96 (95% CI, 0.86 to 1.06), 0.95 (95% CI, 0.86 to 1.03) and 1.00 (95% CI, 0.91 to 1.09). CONCLUSIONS: Plasma concentrations of nilotinib could be predicted on the basis of DBS. DBS sampling to assess nilotinib concentrations in CML patients seems a suitable alternative for venous sampling.

An UPLC-MS detection method for the quantification of five antibiotics in human plasma.

BACKGROUND: An UPLC-MS detection method for the quantification of amikacin, flucloxacillin, meropenem, penicillin G and vancomycin was developed and validated. RESULTS: The calibration curves were found to be linear from 0.47 to 50 mg/l for amikacin, 1.28 to 135 mg/l for flucloxacillin, 0.75 to 80 mg/l for meropenem, 0.38 to 80 mg/l for penicillin G and 0.73 to 80 mg/l for vancomycin. Between- and within-run accuracy was ranged between 85 and 115%. Between and within imprecision expressed as CV was within 15%. CONCLUSION: The validated method was successfully applied to a PK study in very preterm and small for gestational age infants treated for nosocomial sepsis and/or meningitis.

Therapeutic drug monitoring by dried blood spot: progress to date and future directions.

This article discusses dried blood spot (DBS) sampling in therapeutic drug monitoring (TDM). The most important advantages of DBS sampling in TDM are the minimally invasive procedure of a finger prick (home sampling), the small volume (children), and the stability of the analyte. Many assays in DBS have been reported in the literature over the previous 5 years. These assays and their analytical techniques are reviewed here. Factors that may influence the accuracy and reproducibility of DBS methods are also discussed. Important issues are the correlation with plasma/serum concentrations and the influence of hematocrit on spot size and recovery. The different substrate materials are considered. DBS sampling can be a valid alternative to conventional venous sampling. However, patient correlation studies are indispensable to prove this. Promising developments are dried plasma spots using membrane and hematocrit correction using the potassium concentration.

Toxicokinetics of a dipyridamole (Persantin) intoxication: case report.

We report a case of a 51-year-old woman who was admitted to the hospital after ingestion of large doses of dipyridamole (12 g), temazepam (1 g) and oxazepam (0.2 g) with suicidal intent. The highest dipyridamole concentration that was measured in serum was 9.2 mg/L, which was paralleled by impaired platelet activation. For temazepam and oxazepam, peak serum concentrations were 8.5 and 1.3 mg/L, respectively. The patient was treated with activated charcoal, magnesium sulfate and aminophylline and could be discharged in good physical condition within 17 hours. This is the first report that provides toxicokinetic data and a corresponding pharmacodynamic effect after an intoxication with dipyridamole.

Impact of gestational age and birth weight on amikacin clearance on day 1 of life.

BACKGROUND AND OBJECTIVES: Intrauterine growth restriction (IUGR) and prematurity are associated with a low nephron endowment. It can therefore be expected that neonates who are born premature and/or after IUGR have a lower GFR. Measurement of GFR in neonates is difficult, but the clearance of amikacin has been proven to be a reliable marker. We hypothesized that amikacin clearance is lower after IUGR or premature birth as a marker of low nephron endowment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Amikacin clearance was retrospectively analyzed in 161 neonates who received amikacin within the first 24 h of life. Using the MW/Pharm computer program, a population one-compartment model was calculated. The mean population pharmacokinetic parameters were individualized for each patient according to the maximum a posteriori Bayesian fitting method and provided the amikacin clearance. RESULTS: Our results show that birth weight z score and gestational age are correlated with the clearance of amikacin (partial correlation coefficient 0.159, P = 0.046, and 0.396, P < 0.001, respectively), after correction for other factors. CONCLUSIONS: We conclude that renal clearance on the first day of life is lower in neonates with a lower gestational age and/or birth weight z score. This indicates that both prematurity and IUGR impair GFR on the first day of life.