Dosing optimization of amoxicillin in children treated for Lyme disease
Anne Ravix (1), Verena Gotta (2,3), Paolo Paioni (3,4), Marc Pfister (2,3), Monia Guidi (1,5,6,*), Chantal Csajka (1,3,6,7,*)
(1) Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (2) Division of Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland. (3) SwissPedDose/SwissPedNet collaboration expert team, Zurich, Switzerland. (4) Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland. (5) Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (6) Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva & Lausanne, Switzerland. (7) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. (*) Equal contribution
Context and objectives: Amoxicillin is a beta-lactam antibiotic prescribed to children to treat erythema migrans (EM), an early-localized manifestation of Lyme disease caused by the spirochete Borrelia burgdorferi sensu latu. In Switzerland, the recommended dosage regimen for children aged from 1 month to 18 years is 50 mg/kg/day divided into 3 doses (t.i.d) given orally with a maximum daily dose of 1500 mg. However, such a t.i.d regimen is difficult to implement due e.g. to the complexity of administering the medication to the child, the responsibility of the parent, and/or the third-party intervention at school. Alternative administration of amoxicillin twice a day (b.i.d), already routinely recommended for the treatment of other infections such as pneumonia or otitis media based on efficacy studies, could facilitate the EM treatment and increase medication adherence [1-3]. Efficacy studies would be, however, very challenging in the context of EM, since this skin condition resolves spontaneously even without treatment, while the infection may persist, and cause disseminated Lyme disease months or even years later. The objective of this model-based simulation study was to verify whether a dose of 50 mg/kg/day given b.i.d dosing provides an amoxicillin exposure coverage comparable to that with the current recommended yet less convenient t.i.d dosing schedule.
Methods: Model-based simulations were performed adapting a popPK model previously developed on adult data to children, using appropriate allometric bodyweight scaling functions on both apparent clearance and volume of distribution [4, 5]. These simulations were conducted on a virtual population of 15,000 children, with bodyweight ranging from 4 to 80 kg, who received the usual dosage regimen of 50 mg/kg divided into three (i.e., 16.67 mg/kg t.i.d) and two doses (i.e., 25 mg/kg b.i.d). Additional b.i.d regimens from 30 to 50 mg/kg b.i.d with a 5 mg/kg step were tested. As for all time-dependent antibiotics, amoxicillin therapeutic target was defined as the percentage of time the free concentration remains over the minimal inhibitory concentration (% ft>MIC). Two common therapeutic targets were selected: 40% and 50% ft>MIC with various MICs reported for Borrelia burgdorferi sensu latu (0.06, 0.25, 1, 2 and 4 mg/L) [6-8]. Dosage regimens were compared by calculating the probability of target attainment (PTA) for each MIC, which was considered acceptable if it remained above 50%. The bioequivalence criterion was additionally used, checking whether the ratio between the log-transformed daily area under the curve (AUC0-24h) of b.i.d regimens to the reference regimen (i.e., 16.67 mg/kg t.i.d) was within the bioequivalence range of [80%, 125%] [9].
Results: The bioequivalence criterion was satisfied for all b.i.d regimens compared to t.i.d dosing. The PTA for both therapeutic targets with a 50 mg/kg/day dose t.i.d or with all the tested b.i.d regimens, including the 25 mg/kg b.i.d, was greater than 50% for MIC ≤ 1 mg/L. For MIC = 2 mg/L, PTA was less than 50% for the 50% ft>MIC target with the 25 mg/kg b.i.d regimen (43% versus 61% with t.i.d regimen) and a dose of 30 mg/kg b.i.d was necessary to achieve a PTA > 50%. For MIC = 4 mg/L, PTAs were low in both regimens (less than 32% for the t.i.d regimen and 27% for b.i.d regimen), only a dose of at least 45 mg/kg b.i.d achieved a PTA > 50%.
Conclusions: According to model-based simulations, bactericidal activity of amoxicillin could be achieved for the treatment of EM in a majority of children treated with 25 mg/kg b.i.d assuming a MIC between 0.06 mg/L and 1 mg/L for Borrelia burgdorferi sensu latu. This regimen should be preferred in children in order to simplify treatment and enhance adherence. A slight difference was observed in PTAs obtained according to these two doses with MIC = 2 mg/L, for which our results suggest increasing the twice-daily dose to 30 mg/kg b.i.d. For MIC = 4 mg/L, a dose of at least 45 mg/kg b.i.d is required to have a PTA > 50%.
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