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Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats
Imène Boujemla1, May Fakhoury2, Michel Nassar1
1PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
Background:
Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects, mental retardation and non-genetic sensorineural hearing loss. Murine models have been developed in order to understand the pathophysiological mechanisms underlying these lesions. These models are being proposed for the validation of therapeutic protocols for clinical use. The aim of this preclinical study was to assess the pharmacokinetics of the reference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm the diffusion of the molecule to the appropriate target zones.
Methods:
Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats. Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days of intraperitoneal injection of ganciclovir. The occurrence of hematological side effects of ganciclovir was evaluated in the different blood cell lineages.
Results:
In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of ganciclovir showed a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in ganciclovir-treated newborn mice.
Conclusion:
Our data provide evidence for the intracochlear diffusion of the molecule, which may be relevant for the treatment of sensorineural hearing loss in congenitally-infected children.
Insights
Ganciclovir effectively reaches the cochlea in animal models, suggesting potential for treating congenital cytomegalovirus (CMV) hearing loss. However, newborn mice showed significant blood cell count reductions, indicating potential side effects.
Area of Science:
- Virology
- Pharmacology
- Otolaryngology
Background:
- Congenital cytomegalovirus (CMV) infection is a primary cause of non-genetic sensorineural hearing loss and birth defects.
- Murine models are crucial for understanding CMV pathogenesis and validating antiviral therapies.
- Ganciclovir is the reference antiviral drug for CMV, necessitating pharmacokinetic studies for optimized treatment protocols.
Purpose of the Study:
- To assess the pharmacokinetics of ganciclovir in preclinical models.
- To confirm ganciclovir's diffusion into target zones, including the cochlea and across the placenta.
- To optimize therapeutic protocols for congenital CMV infection.
Main Methods:
- Evaluated transplacental and intracochlear diffusion of ganciclovir in mice and rats.
- Assessed ganciclovir pharmacokinetics in adult mice and pups following daily intraperitoneal injections.
- Monitored hematological side effects in various blood cell lineages.
Main Results:
- Ganciclovir achieved blood concentrations within the cochlea in adult rats.
- Transplacental diffusion was confirmed in gestating mice, with a fetal-to-maternal ratio of 0.5.
- Newborn mice exhibited significant decreases in white blood cells, red blood cells, and platelets after ganciclovir treatment.
Conclusions:
- Ganciclovir demonstrates effective intracochlear diffusion, relevant for treating CMV-induced sensorineural hearing loss.
- The findings support ganciclovir's potential role in managing congenital CMV infection.
- Potential hematological side effects in newborns require careful consideration for clinical application.
