Erlotinib and pantoprazole: a relevant interaction or not?

AIMS: There is increasing evidence that erlotinib exposure correlates well with treatment outcome. In this report we present a case of therapeutic drug monitoring of erlotinib in a patient with a gastric ulcer, treated with the proton pump inhibitor pantoprazole. This agent may cause an unwanted, but not always unavoidable, interaction since absorption of erlotinib is pH dependent. METHODS: Erlotinib trough concentrations were monitored in a patient during treatment with orally and intravenously administered pantoprazole. RESULTS: Erlotinib trough concentrations were diminished during high dose intravenously administered pantoprazole, but returned to normal when the dose was reduced and pantoprazole was administered orally. CONCLUSIONS: More studies are needed to assess the dose dependency of the interaction between pantoprazole and erlotinib. Furthermore, we advise to monitor closely erlotinib plasma concentrations and adjust the erlotinib dose accordingly when a clinically relevant interaction is suspected and no proper dosing guidelines are available.

Serum concentrations of psychotropic drugs in neonates as a PROgnOstic Factor for admission to the neonatology ward and withdrawal symptoms: PROOF-1.

The aim is to determine whether serum drug concentrations obtained from the neonate's umbilical cord can be used as a prognostic factor for admission to the neonatology ward and the occurrence of withdrawal symptoms. A retrospective observational monocenter cohort study was carried out among pregnant women using psychotropic drugs and their baby. Binary logistic regression was used for the multivariate analysis. Of the 186 neonates included, 22.6% (n=42) were admitted to the neonatology ward, 6.5% (n=12) because of withdrawal. Among women with therapeutic concentrations of psychotropic medication, 22.0% (n=5) of the neonates had withdrawal symptoms. When comparing neonates with therapeutic versus undetectable drug concentrations, an odds ratio of 3.1 (95% confidence interval: 1.1-8.6) was found for admission to the neonatology ward and an odds ratio of 20.5 (95% confidence interval: 2.2-186.1) for the occurrence of withdrawal symptoms. Therapeutic concentrations of psychotropic drugs in neonates' umbilical cord blood correspond with higher odds for admission to the neonatology ward and the occurrence of withdrawal symptoms compared with neonates with undetectable drug concentrations. The measurement of drug concentrations in the neonate may contribute toward the general clinical assessment of the physician to predict the necessity of admission to the neonatology ward and the risk of withdrawal symptoms.

Entrapment by Cremophor EL decreases the absorption of paclitaxel from the gut.

BACKGROUND: Recent studies in mice and patients have shown that the low oral bioavailability of paclitaxel can be increased by coadministration of P-glycoprotein blockers. However, in patients an increase in the oral paclitaxel dose from 60 to 300 mg/m(2) does not result in proportionally higher plasma levels. We hypothesized that the surfactant Cremophor EL, present in the formulation of paclitaxel, may be responsible for this nonlinear absorption by entrapping paclitaxel within the intestinal lumen, probably by inclusion in micelles. METHODS: Paclitaxel was administered to mdr1ab P-glycoprotein knockout mice with either the conventional (controls) or a seven-fold higher amount of Cremophor EL (test group). Plasma, gastrointestinal tissues with their contents and faeces were collected and analysed by high-performance liquid chromatography to determine the levels of paclitaxel and Cremophor EL. The critical micellar concentrations of Cremophor EL in the contents of the small intestine were also established by an in vitro assay. RESULTS: Paclitaxel recoveries in the faeces of the control and test groups were 7.6% and 35.8%, respectively. The peak plasma level and plasma AUC were reduced in the test group by about 75% and 40%, respectively. Only in mice from the test group did substantial quantities of paclitaxel together with Cremophor EL reach the caecum, thus passing through the small intestine. The concentration of Cremophor EL in the distal part of the small intestine and the caecum was 15 times higher in the test group and well above the critical micellar concentration of Cremophor EL. CONCLUSIONS: These results show that Cremophor EL prevents efficient uptake of paclitaxel from the gut, probably by entrapment within micelles. Other formulations should be developed for oral therapy with paclitaxel.

The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children.

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.

Phase II and pharmacological study of oral docetaxel plus cyclosporin A in anthracycline pre-treated metastatic breast cancer.

INTRODUCTION: Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer. MATERIALS AND METHODS: Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9. RESULTS: Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 - 32). The overall response rate in evaluable patients was 42% (95% CI: 23 - 63) and the median overall survival was 12.2 months (8.4 - 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9. CONCLUSION: Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.

Bench to bedside development of GMP grade Rhenium-188-HEDP, a radiopharmaceutical for targeted treatment of painful bone metastases.

Bone-targeting therapeutic radiopharmaceuticals are effective agents for treatment of painful bone metastases. Rhenium-188-HEDP is such a therapeutic radiopharmaceutical and has advantages over commercially available alternatives in terms of efficacy, safety and the ability to be produced on-site, allowing rapid treatment upon presentation of patients with pain. Unlike many other radiopharmaceuticals, there are no standardized preparation methods for Rhenium-188-HEDP. It is known, however, that drug composition may not only affect stability of the final drug product, but it may also influence bone affinity and, thus, efficacy. Furthermore, for support of clinical studies with Rhenium-188-HEDP as an investigational medicinal product, preparation of this radiopharmaceutical has to be performed under GMP conditions. To our knowledge, no group has reported on the preparation of Rhenium-188-HEDP under GMP conditions or on stock production of sterile non-radioactive starting materials. We present the production of GMP grade Rhenium-188-HEDP for application of this therapeutic radiopharmaceutical in routine clinical practice and for support of clinical studies. In addition, bio-distribution data of Rhenium-188-HEDP in mice and in patients with bone metastases originating from prostate cancer are presented.

Amitriptyline cream ingestion in a 1-year-old boy.

A 1-year-old boy presented to the emergency department with drowsiness after intoxication from amitriptyline cream. The amitriptyline level in his blood was in the high-therapeutic range for adults. He was admitted for cardiac monitoring. Except for a short episode with irregular heart rate, he recovered completely within 24 hours without adjuvant treatment. Amitriptyline is known as an antidepressant but is also prescribed for neuropathic pain. It is usually prescribed in tablet form; the cream is a novel application. In children, intoxication with amitriptyline may cause drowsiness, seizures, coma, hypotension, tachycardia, and life-threatening cardiac arrhythmias. This is the first case report presenting intoxication in a child with amitriptyline cream. It stresses the importance of keeping children away from the medicine cabinet, even from creams or ointments.

Development of an optimal lidocaine infusion strategy for neonatal seizures.

INTRODUCTION: Lidocaine is an effective drug for the treatment of neonatal convulsions not responding to traditional anticonvulsant therapy. However, one of the side-effects is a risk of cardiac arrhythmias. The aim of this study was to develop an optimal dosing strategy with minimal risk of cardiac arrhythmias. MATERIALS AND METHODS: As a first step, we studied 20 neonates during routine treatment of neonatal seizures with lidocaine. All were given a loading dose of 2 mg/kg in 10 min, followed by the continuous infusion of 6 mg/kg per hour for 12 h, 4 mg/kg per hour for 12 h and finally 2 mg/kg per hour for 12 h. Effectiveness, cardiac toxicity and lidocaine plasma concentrations were then determined. RESULTS: No cardiac arrhythmias were observed, and lidocaine was effective in 76% of the treatments. In most of the treatments (13 out of 20) maximal lidocaine plasma concentrations were >9 mg/L. Plasma levels >9 mg/L have been related to cardiac toxicity when used as an anti-arrhythmic drug in adults. It was of interest that all preterm infants showed high lidocaine plasma levels. Secondly, we developed the optimal dosing regimen, which was defined as an infusion regimen at which maximal lidocaine plasma concentrations are <9 mg/L. Simulations with the developed pharmacokinetic model indicated a reduction in the infusion duration of lidocaine at 6 mg/kg per hour from 12 to 6 h. Thirdly, the new lidocaine dosing regimen was evaluated. Fifteen neonates (16 treatments) were studied. No cardiac arrhythmias were observed, and lidocaine was effective in 78% of the treatments. In most of the treatments (11 out of 16) maximal lidocaine plasma concentrations were <9 mg/L. Again preterm infants showed relatively high lidocaine plasma levels. CONCLUSION: A new lidocaine dosing schedule was developed. This new regimen should have a lower risk of cardiac arrhythmias and appears to be as effective in term infants. For preterm infants the optimal regimen needs to be determined.