Dataset Information

Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection.

ABSTRACT: Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. A target area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 50 ?g · h/ml is recommended. The standard dose has resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization for this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach. The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC0-24 to ensure its efficacy. A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC0-24 after being given the standard dose. For all the subtherapeutic patients (achieving <80% of the target AUC) (n = 5), a model-based dosage adjustment was performed using the Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased by 28.6% to 60.0% in these five patients, and all adapted AUC0-24 values achieved the target (range, 48.6 to 66.1 ?g · h/ml). The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. The population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinically feasible method to adapt the ganciclovir dose in neonatal clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT03113344.).

SUBMITTER: Dong Q

PROVIDER: S-EPMC5923132 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection.

Dong Qian Q Leroux Stephanie S Shi Hai-Yan HY Xu Hai-Yan HY Kou Chen C Khan Muhammad Wasim MW Jacqz-Aigrain Evelyne E Zhao Wei W

Antimicrobial agents and chemotherapy 20180426 5

Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. A target area under the concentration-time curve from 0 to 24 h (AUC<sub>0-24</sub>) of 40 to 50 μg · h/ml is recommended. The standard dose has resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization for this vulnerable popul ...[more]

PMID: 29507070

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Project description:PurposeTo investigate the intra-cameral level of ganciclovir following topical application of ganciclovir gel, 0.15% for cytomegalovirus (CMV) anterior segment infection.DesignNon-randomized, prospective, interventional clinical study.MethodsPatients with active CMV anterior segment infection seen at Singapore National Eye Centre, confirmed by positive CMV real time PCR (RT-PCR) of the aqueous humor, that had not been treated with any form of ganciclovir in the preceding 1 month were recruited. They were treated with ganciclovir gel, 0.15% 1cc 5 times a day. Following 6 weeks of treatment, CMV load in the aqueous humor was measured using CMV RT-PCR and the ganciclovir drug levels in tears and aqueous humor were measured using high-performance liquid chromatography-mass spectrometry. The clinical features of the disease activity and the central corneal thickness (CCT) were recorded at the baseline and post-treatment.ResultsThere were 29 eyes of 29 patients, of which 23 eyes had CMV anterior uveitis and 6 eyes had CMV endotheliitis. At the end of week 6, 26 eyes had undetectable CMV titre in the aqueous humor and no anterior chamber (AC) activity. Two patients had an increased CMV titre and increased AC inflammation. Both of these patients were non-compliant with the treatment. One patient had a reduced CMV titre in the aqueous humor with minimal AC inflammation. The mean ganciclovir concentration in the aqueous humor and the tears were 17.4 ± 30.6 ng/ml and 20,420.9 ± 33,120.8 ng/ml respectively. Mean CCT was 552.2 ± 42.3 microns. There was a weak correlation between the ganciclovir concentration in the aqueous humor and CCT (Spearmen's r = + 0.42, p = 0.025). There was no significant correlation between the ganiclovir concentration in the tears and CCT (Spearmen's r = + 0.39, p = 0.11).ConclusionGanciclovir levels in the aqueous humor was below the 50% inhibitory dose (ID50) for CMV replication, following topical application of the ganciclovir gel, 0.15%.Trial registrationSingHealth Centralized Institutional Review Board, Singapore; R733/17/2010, ClinicalTrials.gov; NCT01647529.

Dataset Information

Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection.

Publications

Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection.

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