Françoise Livio

Systemic exposure to tobramycin after local antibiotic treatment with calcium sulphate as carrier material

IntroductionOsteoset® T is a calcium sulphate void filler containing 4% tobramycin sulphate, used to treat bone and soft tissue infections. Despite systemic exposure to the antibiotic, there are no pharmacokinetic studies in humans published so far. Based on the observations made in our patients, a model predicting tobramycin serum levels and evaluating their toxicity potential is presented.MethodsFollowing implantation of Osteoset® T, tobramycin serum concentrations were monitored systematically. A pharmacokinetic analysis was performed using a non-linear mixed effects model based on a one compartment model with first-degree absorption.ResultsData from 12 patients treated between October 2006 and March 2008 were analysed. Concentration profiles were consistent with the first-order slow release and single-compartment kinetics, whilst showing important variability. Predicted tobramycin serum concentrations depended clearly on both implanted drug amount and renal function.Discussion and conclusionDespite the popularity of aminoglycosides for local antibiotic therapy, pharmacokinetic data for this indication are scarce, and not available for calcium sulphate as carrier material. Systemic exposure to tobramycin after implantation of Osteoset® T appears reassuring regarding toxicity potential, except in case of markedly impaired renal function. We recommend in adapting the dosage to the estimated creatinine clearance rather than solely to the patient’s weight.

Imatinib-induced dose-dependent interstitial lung disease successfully switched to nilotinib: a case report with concentration exposure data

Imatinib mesylate (Glivec , Novartis) is the first tyrosine kinase inhibitor (TKI) approved for the treatment of patients with chronic myeloid leukemia (CML), and it has radically changed the prognosis of this disease. In some patients, however, suboptimal response and therapeutic failure is observed. In such cases, either imatinib dosage increase or change to a second-generation TKI is recommended [1]. The ability to escalate dosage may be limited by the risk of adverse drug reactions (ADR), as observed in the present case. The patient showed suboptimal response and low systemic exposure under imatinib 400 mg daily, and developed reversible acute interstitial pneumonitis (IP) immediately after the dosage was increased. There was no recurrence after subsequently switching to nilotinib (Tasigna , Novartis). A 62-year-old woman with unremarkable medical history other than a gastric bypass in 2006 (current BMI 28 kg/m) was diagnosed with a high Sokal score Philadelphia chromosome-positive (Ph) chronic phase CML in October 2010. She was initially treated with imatinib 400 mg daily, which was well tolerated. Complete hematological response was rapidly achieved, but after about 3 months, due to minimal cytogenetic (Ph 95 %) and absence of molecular responses, together with very low imatinib plasma concentration at 379 lg/L (C24h), dosage was increased to 300 mg twice daily. Mutation of the tyrosine-kinase domain, and other causes of resistance and drug interaction were excluded. The patient claimed to have fully complied with the treatment regimen. Approximately 2 weeks later the patient reported new grade II dyspnea and cough. Physical examination was unremarkable, and oxygen saturation was 94 % on room air. Pulmonary function tests showed a mild restrictive disease. A thoracic computed tomography scan revealed bilateral small pseudo-nodular lesions, predominantly in the lower and middle right lobes (Fig. 1a). Broncho-alveolar lavage showed lymphocytic alveolitis with 290,000 cells/mL, 55 % macrophages, 36 % lymphocytes (predominantly T lymphocytes: 88 % CD3), 5 % neutrophils, and 0 % eosinophils, without any bacteria, mycobacteria, fungi, viruses, or malignant cells. Accordingly, drug-induced interstitial lung disease was suspected and imatinib discontinued in February 2011. Shortness of breath and cough resolved within a couple of weeks after imatinib discontinuation and short-course prednisone therapy; oxygen saturation rose to 98 % on room air. Partial radiological resolution was observed after 3 weeks (Fig. 1b), and complete at 10 weeks (Fig. 1c). The switch to nilotinib 400 mg twice daily was well tolerated and followed by complete cytogenetic and major molecular response sustained at 1 year. Pulmonary symptoms arose rapidly after an increase to the patient’s imatinib dosage, and were fully reversible after the drug was discontinued. This is highly suggestive of a dose-dependent ADR. Pulmonary infection was K. Dao T. Buclin Division of Clinical Pharmacology, Biomedicine, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

Guidance to develop individual dose recommendations for patients on chronic hemodialysis

ABSTRACT Introduction: In addition to tailored clinical trials in patients on chronic hemodialysis (HD) during drug development, clinician-initiated post-marketing studies and case reports on individual pharmacokinetic (PK) assessments provide an important source of information about drug dialysability and individualized dose recommendations in this vulnerable population. Areas covered: First, factors that may alter drug exposure in HD patients are explained. Second, available regulatory and methodological guidelines for PK assessments in this population are summarized. Third, a 4-step approach is proposed to develop individual dose recommendations for HD patients receiving drugs without data from a PK study: (1) literature search, (2) model-based dosage decisions, (3) validation and refinement through concentration monitoring, and (4) publication of relevant observations. Fourth, clinician-initiated PK assessments and case reports to evaluate and individualize use of drugs in HD patients are reviewed, and recommendations to enhance their quality are discussed. Expert commentary: Guidance on collecting and reporting PK information in individual HD patients is warranted to ensure completeness and consistency of such PK studies. A checklist and template for easy-to-implement PK calculations and pharmacometric modeling is provided to facilitate evaluation and individualization of dosing strategies in these patients.

Pharmacokinetic modelling of dialytic clearance in a case of acyclovir intoxication

We report a patient with severe acyclovir intoxication who was uccessfully managed with haemodialysis. In such situations, the umber of sessions is mostly based on clinical judgement. We retospectively developed a pharmacokinetic (PK) model to describe cyclovir clearance in haemodialysis. This model was validated by easuring acyclovir levels before and after the first two haemodialsis sessions. A 66-year-old man was hospitalised for herpes encephalitis. ntravenous (i.v.) acyclovir was started at standard dosage of 0 mg/kg three times daily (plasma creatinine 97 mol/L). Intraenous hydration initiated on Day 1 was stopped on Day 5 despite nsufficient oral fluid intake. On Day 8 the patient became anuric nd increasingly confused. His plasma creatinine was 468 mol/L. e was diagnosed with acyclovir-induced kidney injury and subseuent intoxication. Acyclovir was stopped and 3-h haemodialysis essions were performed on Days 8, 9 and 10 using a cenral catheter (dialysate flow rate 500 mL/min; blood flow rate 00 mL/min during the first session, 250 mL/min during the last essions). The patient’s mental status already improved after the rst session and reversibility was complete after the third session. iuresis slowly resumed on Day 9 and plasma creatinine was 30 mol/L on Day 15. Acyclovir re-started at a lower dosage was ell tolerated. A PK model was developed based on estimated acyclovir learance during haemodialysis (CLE) to simulate plasma concenrations, using published acyclovir PK parameters, the patient’s enal status and the dialysis settings. Acyclovir normal clearance CL), extrarenal elimination fraction (Q0), volume of distribution V), unbound fraction (fu) and blood–plasma partition coefcient were obtained from the literature [1–3], as follows: L = 12 L/h; V = 60 L (0.66 L/kg × 90 kg); Q0 = 0.08; fu = 0.85; and acylovir blood/plasma partition coefficient = 1.1. Acyclovir CLE (L/h) was equated to the sum of renal clearance CLR), non-renal clearance (CLNR) and dialytic clearance (CLDial):