Sunitinib for the treatment of metastatic gastrointestinal stromal tumors: the effect of TDM-guided dose optimization on clinical outcomes.

BACKGROUND: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity. PATIENTS AND METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing. RESULTS: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002). CONCLUSIONS: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.

Linezolid-Induced Thrombocytopenia in Patients with Renal Impairment: A Case Series, Review and Dose Advice.

BACKGROUND AND OBJECTIVE: Oral linezolid is often used as alternative therapy for intravenous vancomycin. According to the current guidelines, no dose adjustment has to be made in case of renal impairment. Nevertheless, in our hospital we have seen several patients with renal impairment who developed linezolid-induced thrombocytopenia when linezolid was taken in the standard dose. In this case series and review we want to emphasize the necessity of reviewing the Dutch and international guidelines. METHODS: We describe five cases with renal impairment that developed linezolid-induced thrombocytopenia in our hospital. A PubMed literature review was conducted to identify other cases and find the optimal dosing regimen for these patients. RESULTS: Our cases join a long list of cases and available literature about linezolid-induced thrombocytopenia in patients with renal impairment. Less linezolid-induced thrombocytopenia was found, both in our cases and in the literature, after dose reduction of 50%. High linezolid trough concentrations were associated with a higher risk of linezolid-induced thrombocytopenia. Besides renal impairment, other risk factors for developing linezolid-induced thrombocytopenia were also identified, such as low body weight, high daily dose/kg, higher age, longer duration of therapy, low baseline count, malignity, low-dose aspirin and interacting co-medication. CONCLUSION: Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2 days of standard dosing for all patients with an estimated glomerular filtration of <60 mL/min/1.73 m2. Besides this, therapeutic drug monitoring and thrombocytes monitoring may be executed weekly when patients have renal impairment or other risk factors for developing linezolid-induced thrombocytopenia.

Pharmacy compounded pilocarpine: An adequate solution to overcome shortage of pilogel® discs for sweat testing in patients with cystic fibrosis.

To respond to shortage of pilocarpine discs due to CE-licensing problems a pharmacy compounded pilocarpine HCL solution was developed and validated for use in CF diagnosis. The aim of this study was to compare the results from a pharmacy compounded pilocarpine HCL solution versus Pilogel® discs for the measurements of sweat chloride concentrations. Ten pediatric and adult patients with CF underwent a sweat test using both Pilogel® discs and pilocarpine HCL solution. The average difference between both methods was -3.25 mmol/L (95% Limits of Agreement: -7.19 [95% CI: -9.19;-5.19] and 0.69 [95% CI: -1.31;2.69] mmol/L. Passing-Bablok regression showed that zero was enclosed with the 95% CI of the calculated intercept (0.15 [95% CI: -1.70;1.42] mmol/L). These data show a good agreement in chloride concentrations obtained using the two pilocarpine products. Therefore, the pharmacy compounded pilocarpine HCL solution can be used as an alternative for Pilogel® discs during times of shortage.

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review.

BACKGROUND AND OBJECTIVE: Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib. METHODS: Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded. RESULTS: Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations. CONCLUSION: Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.

Extending the viability of human precision-cut intestinal slice model for drug metabolism studies.

Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media [expansion medium (Emed) and differentiation medium (Dmed)]. After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.

The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis.

OBJECTIVES: To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF). METHODS: A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20-30 and 20-40 mg/L) and AUC0-24 (80-120 and 80-150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0-24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined. RESULTS: More patients achieved standard Cmax and AUC0-24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0-24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0-24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0-24 targets. CONCLUSIONS: A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0-24 ranges were narrower and the incidence of high AUC0-24 values was lower. Height-based doses should therefore be considered for patients with CF.

[Fosfomycin, an old antibiotic with new possibilities]. / Fosfomycine, een oud antibioticum met nieuwe mogelijkheden.

- Fosfomycin is a broad-spectrum antibiotic agent used orally for uncomplicated cystitis. The intravenous form of administration has recently been authorised in the Netherlands.- Thanks to its broad spectrum and extensive tissue penetration, fosfomycin offers possibilities for the treatment of infections in different organs.- Infections with multidrug-resistant bacteria pose a significant threat to public health. Many of these multidrug-resistant bacteria are sensitive to fosfomycin, which means fosfomycin may be an option for the treatment of infections with multidrug-resistant bacteria. - There is a lack of knowledge about the pharmacological properties of fosfomycin to establish a good dosing schedule. Knowledge is also lacking about the safety of fosfomycin and the extent of its tolerability in the treatment of different infections. - More research is needed before fosfomycin can be used in the battle against multidrug-resistant bacteria.

Pharmacokinetics and Tolerability of Once Daily Double Dose Tobramycin Inhalation in Cystic Fibrosis Using Controlled and Conventional Nebulization.

BACKGROUND: Better treatment outcomes in cystic fibrosis (CF) may be expected by changing standard twice daily (BID) tobramycin inhalation with the conventional nebulizer to once daily (OD) inhalation at double the standard BID dose with a controlled-inhalation nebulizer. We aimed to determine the pharmacokinetics and tolerability of inhaled double-dose tobramycin with the controlled-inhalation AKITA(®) and conventional PARI-LC(®) Plus nebulizer in patients with CF. METHODS: Randomized, open label, crossover study. Pharmacokinetics were assessed in 10 adult CF patients following inhalation of tobramycin (Bramitob(®)) at double the recommended BID dose with the AKITA (300 mg fill dose) and PARI-LC Plus (600 mg fill dose). RESULTS: No significant differences were found in pharmacokinetic parameters between the two nebulizers. Median maximum serum levels were 3.44 (2.25-5.49) and 2.84 (0.82-6.63) mg/L for AKITA and PARI-LC Plus, respectively. Trough serum levels were very low for both nebulizers: 0.03 (0.00-0.09) and 0.02 (0.00-0.06) mg/L for AKITA and PARI-LC Plus, respectively. Time to maximum level was comparable: 0.44 (0.08-0.96) and 0.40 (0.08-0.96) hours for AKITA and PARI-LC Plus, respectively. Serum levels were well below the toxic limit. Inhalations were well tolerated and no serious adverse events occurred. Nebulization time was 33% shorter with the AKITA. CONCLUSIONS: OD tobramycin inhalation of the double standard BID dose with a controlled-inhalation and conventional nebulizer resulted in similar pharmacokinetics in the doses given, with serum levels below the toxic limit. Further research demonstrating clinical efficacy and safety of this treatment approach is required. Dutch trial register number NTR4525.

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison.

BACKGROUND: Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AIM: To investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. METHODS: Children (age 5-18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. RESULTS: Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). CONCLUSIONS: Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

The influence of breathing mode on tobramycin serum levels using the I-neb AAD system in adults with cystic fibrosis.

BACKGROUND: The clinical effectiveness of inhaled tobramycin depends on the dose reaching the desired regions of the lungs. This study evaluates the influence of breathing mode on tobramycin lung deposition using its pharmacokinetics as surrogate for deposition. METHODS: In a randomized, open-label, crossover study lung deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. Patients were categorized in three subgroups according to their lung function: ≤59%, 60-79% or ≥80% of FEV1 predicted. Blood samples were collected in order to model tobramycin pharmacokinetics. Nebulization time was recorded. RESULTS: Inhalation with TIM resulted in significantly higher maximum serum levels and area under the concentration-time curves (0-24h). Mean bioavailability of TIM relative to TBM was 1.53±0.41. Mean nebulization time was reduced by half with TIM. Subgroup category did not affect the results. CONCLUSIONS: Slow and deep inhalation of aerosolized tobramycin resulted in higher lung deposition and shorter nebulization time compared to tidal breathing, regardless of the disease severity of the CF patient. Dutch trial register number NTR3109.

Presence of medication taken by blood donors in plasma for transfusion.

BACKGROUND AND OBJECTIVES: The TRIP national hemovigilance and biovigilance office receives reports on side-effects and incidents associated with transfusion of labile blood products. Anaphylactic reactions accounted for the largest number of serious transfusion reactions in the period 2008-2012. In most cases, no cause is found for these reactions. TRIP data show that anaphylactic reactions occur relatively frequently with transfusion of plasma or platelet concentrates. Data from blood services show that 10% or more of plasma donors regularly use medication which is permitted under donation guidelines. It is conceivable that medication taken by the donor in plasma for transfusion could cause an anaphylactic transfusion reaction in the recipient. This exploratory study investigated the presence of drugs or drug metabolites in donor plasma. MATERIALS AND METHODS: Samples (5 ml) were taken from thawed, quarantine fresh frozen plasma units (FFP) which had to be rejected for transfusion because of leaks or length of time after thawing. The samples were analysed for approximately 1000 drugs and drug metabolites using a toxicological screening method. RESULTS: Eighty-seven samples were analysed. Toxicological screening was positive in fourteen samples (16%). In eleven samples, one substance was found, and in three samples, the presence of two or three drugs was detected. CONCLUSION: After freezing, storage and thawing of fresh FFP, it is possible to detect medication taken by the donor. Further investigation is recommended to analyse whether donors' medication in plasma can be implicated in some cases of allergic or anaphylactic reactions in transfusion recipients.

Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis.

OBJECTIVES: In cystic fibrosis (CF) patients the paranasal sinuses can constitute a niche for bacteria, which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. The objective of this study was to investigate the systemic absorption of nasally administered tobramycin, colistin (administered as colistin sulfomethate sodium; CMS) and a combination of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. METHODS: Ten adult CF patients performed three different nasal irrigations: 300 mg of tobramycin; 160 mg of CMS; and 300 mg of tobramycin combined with 160 mg of CMS. Serum concentrations of tobramycin and colistin A and B (the main components of colistin) were analysed. Tolerability was measured using a visual analogue scale. Dutch Trial Register: NTR 4008. RESULTS: Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable. All three nasal irrigation solutions were well tolerated with a higher tolerability for CMS compared with tobramycin. CONCLUSIONS: Nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated.

Pharmacogenetics: from bench to byte.

Despite initial enthusiasm, the use of pharmacogenetics has remained limited to investigation in only a few clinical fields such as oncology and psychiatry. The main reason is the paucity of scientific evidence to show that pharmacogenetic testing leads to improved clinical outcomes. Moreover, for most pharmacogenetic tests (such as tests for genetic variants of cytochrome P450 enzymes) a detailed knowledge of pharmacology is a prerequisite for application in clinical practice, and both physicians and pharmacists might find it difficult to interpret the clinical value of pharmacogenetic test results. Guidelines that link the result of a pharmacogenetic test to therapeutic recommendations might help to overcome these problems, but such guidelines are only sparsely available. In 2001, an early step was taken to develop such guidelines for the therapeutic use of antidepressants, and these included CYP2D6-related dose recommendations drawn from pharmacokinetic study data. However, the use of such recommendations in routine clinical practice remains difficult, because they are currently outside the ambit of the clinical environment and are not accessible during the decision-making process by physicians and pharmacists, namely the prescription and dispensing of drugs.

N-acetylcysteine and hemodialysis treatment of a severe case of methyl ethyl ketone peroxide intoxication.

The plastic hardener methyl ethyl ketone peroxide (MEKP) is an unstable peroxide that releases free oxygen radicals. Ingestion of this compound induces widespread liver necrosis that is often fatal, extensive ulceration with subsequent scarring, and stenosis of the proximal digestive tract in survivors. Severe metabolic acidosis occurs due to the accumulation of formic acid and other organic acids inducing neurologic damage, such as optic nerve lesions. A 53-year-old man unintentionally ingested approximately 120 ml of a 33% solution of this compound in dimethylphtalate. The patient was treated with the free radical scavenger N-acetylcysteine to counteract free radical-mediated damage and with hemodialysis to remove accumulated organic acids. Although our patient demonstrated considerable edema and ulceration of the distal esophagus, stomach and duodenum in the acute phase, there was never any sign of liver damage or neurological damage, nor were there any demonstrable lesions in the proximal digestive tract three weeks after the event. Treatment with a combination of N-acetylcysteine and haemodialysis may be a promising therapy for this severe and potentially life-threatening intoxication.

Pharmacokinetics and sputum penetration of azithromycin during once weekly dosing in cystic fibrosis patients.

In this study we examined pharmacokinetics, systemic exposure and sputum penetration of azithromycin (AZM) in CF patients on chronic daily AZM therapy after changing to a once weekly dosing scheme. Eight adult CF patients using AZM 500 mg/day were changed to a once weekly dose of 1000 mg during 3 months. Once per month sputum and blood samples were collected. AZM was quantified in blood plasma and polymorphonuclear neutrophils. The cumulative weekly dose was reduced with a factor of 3.5 (7x500 mg vs. 1x1000 mg weekly). This led to a reduction in area under the curve (AUC+/-S.D.) with a factor of 2.5+/-0.8 in plasma, 2.8+/-0.9 in blood, 2.2+/-1.1 in PMNNs and to a reduction in average sputum concentration with a factor of 3.0 (+/-1.5). At 1000 mg once weekly reduced but still substantial concentrations were achieved in PMNNs and in sputum. Although not significant, a tendency towards less than linear reduction was found. In order to calculate and propose an optimal dosing scheme we need to establish a relation between exposure levels and clinical efficacy.

Guidelines for the management of pregnancy in women with cystic fibrosis.

Women with cystic fibrosis (CF) now regularly survive into their reproductive years in good health and wish to have a baby. Many pregnancies have been reported in the literature and it is clear that whilst the outcome for the baby is generally good and some mothers do very well, others find either their CF complicates the pregnancy or is adversely affected by the pregnancy. For some, pregnancy may only become possible after transplantation. Optimal treatment of all aspects of CF needs to be maintained from the preconceptual period until after the baby is born. Clinicians must be prepared to modify their treatment to accommodate the changing physiology during pregnancy and to be aware of changing prescribing before conception, during pregnancy, after birth and during breast feeding. This supplement offers consensus guidelines based on review of the literature and experience of paediatricians, adult and transplant physicians, and nurses, physiotherapists, dietitians, pharmacists and psychologists experienced in CF and anaesthetist and obstetricians with experience of CF pregnancy. It is hoped they will provide practical guidelines helpful to the multidisciplinary CF teams caring for pregnant women with CF.

[Measures for patients taking psychotropic drugs who undergo elective surgery]. / Maatregelen bij patiënten die psychofarmaca gebruiken en die een electieve operatie moeten ondergaan.

Psychotropic drugs can increase the risk of perioperative complications when given in combination with anaesthesia. Evidence-based guidelines that address this issue are lacking. Consensus-based recommendations were formed for the perioperative management of these patients based on the available literature and a systematic evaluation of perioperative risks by the medical specialists directly involved. Patients who use lithium, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants or clozapine are at risk of experiencing adverse interactions. The anaesthesiology literature recommends discontinuing irreversible MAOIs and lithium in all cases, and tricyclic antidepressants in patients with systemic disorders. With the exception of lithium, the risks of psychiatric relapse or recurrence associated with discontinuation necessitate intensive integrated psychiatric treatment. Continuation of treatment under strict haemodynamic observation may also be an option in some cases. Patients taking selective serotonin reuptake inhibitors (SSRIs) should be observed carefully for psychological instability and physical abnormalities, and clinicians should be aware of medications that could increase the risk of haemorrhage when used in combination with SSRIs. In these cases, a psychiatrist should be consulted. The same is true for patients taking antipsychotic or other antidepressant medication who develop psychological instability or have a systemic disorder. Given the widespread use ofpsychotropic drugs and the seriousness of the associated risks, it is recommended that the decision whether to continue or discontinue psychotropic medication should become a standard component of preoperative assessment.

Population pharmacokinetics of tobramycin administered thrice daily and once daily in children and adults with cystic fibrosis.

BACKGROUND: Tobramycin pharmacokinetics have not been evaluated previously in a large series of data collected in children and adults with CF receiving once (OD) or three times daily (TD) tobramycin. METHODS: Therapeutic drug monitoring data in children and adults with CF who participated in a randomised clinical trial evaluating efficacy and toxicity of OD versus TD tobramycin (TOPIC study) were analysed retrospectively. Population pharmacokinetic models stratified to treatment schedule were created, and individual pharmacokinetic parameters were calculated. RESULTS: In paediatric patients, volume of distribution per kg body weight (V1) was greater with OD treatment compared to TD (0.401+/-0.092 versus 0.354+/-0.041, p=0.003). Elimination rate was reduced in all patients receiving OD tobramycin compared to TD (children: 0.00197+/-0.00027 versus 0.00291+/-0.00041, p<0.001, adults: 0.00252+/-0.00008 versus 0.00322+/-0.00050, p<0.001). Tobramycin V1 decreased with increasing age (R(2)=0.3, p<0.001). CONCLUSIONS: The reduced elimination rate in OD may either be caused by circadian pharmacokinetic behaviour of tobramycin or indicates early renal damage caused by high tobramycin doses not detected by biochemical measurements. However, results of our previous work suggest that OD tobramycin may be less nephrotoxic. The higher V1 in children implies that a relative higher tobramycin dose in these patients is needed for the same target peak serum concentration.