Abstract
Background: Weight-based dosing scalars may give different theophylline exposures in obesity. We evaluated a whole-body PBPK model and compared dosing scalars in an explicitly hypothetical population scenario informed by Saudi BMI estimates published before 2026.
Methods: A 14-compartment model was estimated from Theoph data in 12 adults and evaluated against independent published group means. The former 2026-updated WHO inputs were replaced by the archived NCD-RisC 2024 publication dataset describing 2022 age-standardised BMI categories for Saudi Arabia. Sex-specific log-normal distributions and published height means generated 3,000 virtual adults. A 5 mg/kg intravenous loading infusion and 0.4 mg/kg/h maintenance infusion were simulated under four dosing scalars, with 200 bootstrap uncertainty replicates. These age-standardised inputs define a comparison scenario, not the crude distribution of current Saudi patients.
Results: Held-out concentrations had an absolute average fold error of 1.304. Eight of 14 external metrics met the prespecified 0.8–1.25 criterion; all seven distribution-volume metrics met it, but clearance was underpredicted. In the revised population scenario, 42.7% had obesity and 8.5% had BMI ≥40 kg/m². In that highest class, 74.4% were within 10–20 mg/L at 72 h under TBW dosing (95% parameter uncertainty interval 49.0–98.0), with 22.8% above 20 mg/L. AdjBW gave 61.8% in range (43.9–81.4), 0.4% above and 37.8% below. IBW gave 13.4% in range. Loading with TBW or AdjBW placed all simulated adults in range under the model assumptions.
Conclusions: Changing the weight scalar materially changed simulated exposure. Distribution-volume agreement supports exploratory loading comparisons, while failed clearance qualification prevents reliable maintenance-dose recommendations. Apparent 100% attainment is conditional on the model and incomplete variability representation, not a probability of success in patients. Prospective clinical evaluation and therapeutic drug monitoring remain necessary.
Keywords
- physiologically based pharmacokinetics
- obesity
- theophylline
- dosing scalar
- Saudi Arabia
- model qualification
Declarations
- Ethics approval
- NA
- Consent to participate
- NA
- Consent for publication
- NA
- Funding
- NA
- Competing interests
- NA
- Author contributions
- NA
- Data availability
- NA
- Registration
- NA
- Acknowledgements
- NA
Comments
Commenting requires an account and sign-in.