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Background Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high-dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer duration of prehydration would prevent MTX-induced renal toxicity, we preformed a randomized cross-over study comparing 12-4 hours of hydration before the infusion of HDMTX. Procedures Children with ALL and non-Hodgkin lymphoma that were treated with infusions of HDMTX 5 or 8 g/m(2) were randomized to receive intravenous prehydration 12 or 4 hours before the first HDMTX infusion. Patients alternated between 12 and 4 hours of prehydration in the subsequent HDMTX infusions. Renal toxicity was defined as 50% increase in plasma creatinine after the HDMTX infusion. The plasma MTX concentration was measured during and after the HDMTX infusion to determine if the duration of prehydration would influence the systemic MTX clearance. Results A total of 47 patients (224 HDMTX infusions) with a median age of 4.9 years were included in the study. The duration of prehydration had no effect on MTX induced renal toxicity that occurred in 18.5% of all HDMTX 5 g/m(2) infusions and in 40.0% of all HDMTX 8 g/m(2) infusions. Similar the duration of prehydration had no impact on the systemic clearance of MTX. Conclusion Extending prehydration beyond 4 hours does not reduce the risk of renal toxicity or delayed MTX clearance after infusions with HDMTX 5-8 g/m(2).

Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules used in clinical trials in order to come to a dosing advise which could be generally applicable. We used data from a recently updated Cochrane meta analysis (2011), the reports of clinical trials and pharmacokinetic studies. Based on these data, it was concluded that a dose level of 22-30âmg/kg/week is the lowest dose level with proven efficacy. Due to the extended half-life in patients with CF, the weekly dose of azithromycin can be divided in one to seven dosing moments, depending on patient preference and gastro-intestinal tolerance. No important side effects or interactions with other CF-related drugs have been documented so far. Pediatr Pulmonol. 2012; 47:658-665. © 2011 Wiley Periodicals, Inc.

KuKanich, B., Hubin, M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J. vet. Pharmacol. Therap. 33, 42–49. Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 μg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 μg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

Heparin (100 U/kg bodyweight) was administered as single i.v. injections, and heparin concentration in plasma determined by polybrene titration. Mean concentration half-life was 74.7 min in the normal group (n = 6), 118.6 min in the nephrectomized patients (n = 5), and 97.8 min in the other uraemic patients (n = 6). The differences between the mean values for the normals and for the 2 patient groups were statistically significant (p is less than 0.001 and p approximately 0.2 respectively). Mean anticoagulant half-life (based on thrombin clotting time) was 64.3, 75.8 and 62.7 min in the 3 groups. The differences between heparin concentration half-life and anticoagulant half-life in the 3 groups were statistically significant. These differences may be partly explained by a significant fall in heparin cofactor activity after injection of heparin. There was a strong positive individual correlation between heparin concentration half-life and anticoagulant half-life in the patients (r = 0.94), but not in the normal group (r = 0.31). There was a strong negative individual correlation between heparin tolerance and heparin concentration half-life in the patients (r = -0.84), but no correlation in the normal group. It is concluded that severely impaired renal function has a significant, but moderate influence on heparin elimination.

In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t(1/2)). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation:C=Ae(-alpha t)+Be(-beta t), where A and B are concentration unit-coefficients and alpha and beta are exponential coefficients. The relationships between t(1/2) and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t(1/2).In the current paper new equations have been developed that describe the relationships between the terminal t(1/2) (or t(1/2 beta)) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input).A critical value (CV) equals to the quotient of (1-ln2) and (1-beta/alpha) (CV=(1-ln2)/(1-beta/alpha)=0.307/(1-beta/alpha)) has been derived and was compared with the fraction (f(1)) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f(1)=A/alpha/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1-ln2) and infinity. As long as f(1)CV,MRTt(1/2) and vice versa, and when f(1)=CV, then MRT=t(1/2). Following i.v. infusion and oral administration the denominator of the CV equation does not change but its numerator increases to (0.307+beta T/2) (T-infusion duration) and (0.307+beta/ka) (ka-absorption rate constant), respectively. Examples of various drugs are provided.For every drug that after i.v. bolus shows two-compartment disposition kinetics the following conclusions can be drawn (a) When f(1)0.307, then f(1)CV and thus, MRTt(1/2). (b) When beta/alphaln2, then CV1f(1) and thus(,) MRTt(1/2). (c) When ln2beta/alpha(ln4-1), then 1CV0.5 and thus, in order for t(1/2)MRT, f(1) has to be greater than its complementary fraction f(2) (f(1)f(2)). (d) When beta/alpha(ln4-1), it is possible that t(1/2)MRT even when f(2)f(1), as long as f(1)CV. (e) As beta gets closer to alpha, CV approaches its maximal value (infinity) and therefore, the chances of MRTt(1/2) are growing. (f) As beta becomes smaller compared with alpha, beta/alpha approaches zero, the denominator approaches unity and consequently, CV gets its minimal value and thus, the chances of t(1/2)MRT are growing. (g) Following zero and first order input MRT increases compared with i.v. bolus and so does CV and thus, the chances of MRTt(1/2) are growing.

Hagedorn, H.-W., Meiser, H., Zankl, H., Schulz, R. Elimination of doxepin isomers from the horse following intravenous application. J. vet. Pharmacol. Therap.24, 283–289. The tricyclic antidepressant doxepin, representing a 5:1 mixture of trans- and cis-isomers, owns tranquilizing properties. This compound has been associated with illicit medication of racing horses, and therefore should be considered in doping control. Because analysis of doxepin in equine body fluids has not been documented in the literature, a highly sensitive analytical method was developed to individually monitor the doxepin isomers in blood and urine of horses by the use of gas chromatography/mass spectrometry. Following a dose of 1 mg doxepin-HCl/kg intravenously (i.v.), both the isomers were quantified for up to 24 h in serum of horses (n=4). The β-half-lives of the trans- and cis-isomers were 3.5 and 3.1 h, respectively. The ratio of the trans/cis-isomers was found to be constant (4.7:1) during drug elimination and thus corresponded to the original composition of the antidepressant. Up to 12 h following administration low trans-isomer concentrations in an average range of 2–6 ng/mL were detected in urine of each of the horses, while the cis-isomer was only present in two of four horses for up to 8 and 12 h, respectively. In serum, mean trans-isomer concentrations exceeded urine levels maximally 120-fold after 3 h and at least sixfold after 12 h. As serum exhibits considerably higher concentrations of the doxepin isomers as compared with urine, blood of horses is the recommended body fluid when screening for the antidepressant.

The antiepileptic drug valproate is frequently used in the treatment of manic episodes, either as monotherapy or combined with lithium, carbamazepine, or antipsychotics. Drug interaction with valproate secondary to its ability to inhibit drug elimination, as well as induction of its metabolism by concurrently administered drugs, is commonly reported. In particular, the carbapenem antibiotics have been reported to interact with valproate, resulting in lower valproic acid concentrations and loss of seizure control.1

The disposition kinetics of tylosin tartrate administered intravenously (i.v.) at 10 mg/kg and intramuscularly (i.m.) at 20 mg/kg were studied in normal camels and in the same camels at the end of a 14 day water-deprivation period. After i.v. treatment, serum tylosin concentrations in the water-deprived camels were significantly higher, rate of drug elimination was slower, the volume of distribution was significantly smaller, and total body clearance was significantly slower than in the normal camels. On the other hand, serum drug concentrations were lower in the water deprived camels after i.m. dosing, the mean absorption time was significantly shorter and the i.m. availability was significantly smaller than in the normal camels. Water-deprivation was thought to cause reduced rate of tylosin elimination by the liver, as was shown for antipyrine--a drug which is eliminated from the body exclusively by the liver. Redistribution of tylosin in tissues concomitant with a greater proportion of drug in blood and extracellular fluid of water-deprived camels was suggested as a partial explanation for the higher serum drug levels seen after i.v. dosing. The low i.m. availability observed in the water-deprived camels implies that i.v. is the route of choice for tylosin administration to ill, dehydrated camels.

1 An investigation has been made of the excretion of alpha-methyldopa, alpha-methyldopa sulphate, lorazepam and lorazepam glucuronide in the urine of neonates. 2 The rate of elimination of both the drugs in the newborn is slow compared with the adult rate, and apparent half-life being 3 to 4 times longer than the reported adult values. 3 The newborn appear able to readily metabolise alpha-methyldopa to alpha-methyldopa sulphate and to slowly conjugate lorazepam with glucuronic acid. alpha-Methyldopa tends to be conjugated to a greater extent and lorazepam to about the same or slightly lesser extent in the newborn than in adults. 4 It is postulated that elimination in the neonate is mainly controlled by the rate of renal excretion in the case of alpha-methyldopa and by the rate of conjugation in the case of lorazepam.

Summary: Children require larger relative doses of antiepileptic drugs than adults, and because of the greater patient-to-patient variability among children, an “average” dose is less likely to be correct for a given child. Newborns with convulsions initially have very slow drug elimination; as a group, they also have the widest range of pharmacokinetic values. After the first week of life, drug eliminating mechanisms mature and drug dosage requirements often increase dramatically. Thus in the first 6 weeks of life, intrapatient variation is a significant problem and frequent dosage changes are usually required. Thereafter a given child's kinetics are fairly stable. Infants 2 to 12 months old have the highest rates of drug clearance and often require relative doses that are 3 to 5 times larger than doses for adults. After infancy, relative dosage requirements progressively decline until adult values are reached by 10 to 15 years of age. Newborns, infants, and children, as well as adults, have nonlinear kinetics for phenytoin. Thus a wide range of apparent half-lives occur in children, depending on the phenytoin concentration and other factors. Because the kinetics of antiepileptic drugs are so highly variable in children, antiepileptic drug concentration measurements are an essential aspect of the contemporary treatment of children with epilepsy.