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Developmental pharmacodynamics of cyclosporine
1Department of Pediatrics, University of Missouri-Kansas City, Children's Mercy Hospital, 64108, USA. jmarshall@cmh.edu
Insights
Infants show significantly different cyclosporine (INN, ciclosporin) pharmacodynamics compared to older individuals. Understanding these age-related differences in drug response is crucial for safe pediatric immunosuppressive therapy.
Area of Science:
- Pharmacology
- Immunology
- Pediatrics
Background:
- Cyclosporine (INN, ciclosporin) is a key immunosuppressive drug.
- Pediatric dosing and efficacy can be influenced by age-related physiological differences.
- In vitro studies are essential for understanding drug pharmacodynamics.
Purpose of the Study:
- To investigate the relationship between human development and in vitro cyclosporine pharmacodynamics.
- To compare cyclosporine's effects on cell proliferation and interleukin-2 production across different age groups.
Main Methods:
- Peripheral blood monocytes from 56 subjects (3 months to 39 years) were cultured with varying cyclosporine concentrations.
- Cell proliferation and interleukin-2 concentration were measured using radionuclide DNA tagging and ELISA.
- Pharmacodynamic parameters (Emax, IC50, IC90) were determined and compared between infants, children, preadolescents, and adults.
Main Results:
- Infants exhibited a twofold lower mean IC50 for monocyte proliferation and a sevenfold lower mean IC90 for interleukin-2 expression compared to older subjects.
- Older age groups demonstrated similar mean IC50 and Emax values for monocyte proliferation.
- Experimental conditions did not impact proliferation, but high cyclosporine concentrations reduced monocyte viability.
Conclusions:
- In vitro cyclosporine pharmacodynamics are significantly influenced by age.
- Neglecting age-related differences in cyclosporine response may lead to iatrogenic risks in pediatric patients.
- Further research into age-specific dosing is warranted for optimizing immunosuppressive therapy in children.
Objective:
To determine the relationship between human development and in vitro cyclosporine (INN, ciclosporin) pharmacodynamics.
Methods:
Fifty-six subjects ranging in age from 3 months to 39 years were studied in this prospective laboratory investigation at a university children's hospital and clinical pharmacology laboratory. Peripheral blood monocytes were separated from whole blood and cultured with phytohemagglutinin A (5 microg/mL) and cyclosporine (0, 6.25, 12.5, 25, 50, 100, 500, 1000, 2500, and 5000 ng/mL). Peripheral blood monocytes cultures were assayed for cell proliferation and supernatant interleukin-2 concentration with use of radionuclide DNA tagging and enzyme-linked immosorbent assay, respectively. After concentration-effect modeling, summary pharmacodynamic parameters, including the maximal drug effect (Emax) and cyclosporine concentration at which 50% of maximal effect (IC50) and 90% of maximal effect (IC90), were determined. These parameters were compared between four consecutive subject age groups: infants (0-1 years), children (>1-4 years), preadolescents (>4-12 years), and adults (>12 years).
Results:
The peripheral blood monocytes of the infants showed a twofold lower mean IC50 (peripheral blood monocyte proliferation) and sevenfold lower mean IC90 (interleukin-2 expression) than peripheral blood monocytes from older subjects. The three older age groups were similar with respect to mean IC50 and Emax (peripheral blood monocyte proliferation). Lymphocyte subtype proportions measured in peripheral blood monocytes preparations from each age group were generally similar. The experimental conditions (eg, general anesthesia and cyclosporine solvents) did not affect peripheral blood monocytes proliferation, but the highest experimental cyclosporine concentration (ie, 5000 ng/mL) was associated with decreased peripheral blood monocytes viability.
Conclusions:
Cyclosporine pharmacodynamics in vitro are related to age. This factor, if neglected, may be a source of iatrogenic risk during pediatric immunosuppressive therapy.