Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver

Abstract

Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60 mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non-compartmental pharmacokinetic parameters were as follows: half-life 7.37 ± 1.22 hr; volume of distribution 44.62 ± 11.45 L; area under the curve 14.82 ± 2.71 hr/(μg/mL); and clearance 4.15 ± 0.70 L/hr. Rapid theophylline distribution across the placenta was observed. Maternal non-compartmental pharmacokinetic parameters were as follows: half-life 6.54 ± 2.44 hr; volume of distribution 32.48 ± 9.99 L; area under the curve 16.28 ± 4.53 hr/(μg/mL); and clearance 3.69 ± 1.47 L/hr. Foetal and ewe serum concentration-time profiles were fit together into a 3-compartment population pharmacokinetic model, and parameters were as follows: central volume 1.38 ± 0.11 L; 2nd peripheral compartment volume 3.11 ± 0.29 L; 3rd peripheral compartment volume 60.14 ± 6.02 L; elimination clearance 9.89 ± 0.90 L/hr; distribution clearance between central and 2nd compartment 30.87 ± 2.31 L/hr; and distribution clearance between 2nd and 3rd compartments 13.89 ± 1.11 L/hr. Cytochrome P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7 ± 4.4 versus 42.0 ± 3.6%-bound). Free concentrations were lower in the foetus than in the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity.

Figure 1. Foetal-Maternal Theophylline Time-Concentrations Curves

Comparisons of pharmacokinetic profiles for total theophylline concentrations in foetal and maternal serum, following in utero IV bolus administration of 60mg theophylline to six foetal sheep. Maternal samples were not taken from (a).

Figure 2. Comparison of in vitro serum protein binding of theophylline

The extent of theophylline bound to serum protein (%-bound) was determined in vitro from free and total concentrations of theophylline. A paired-comparison of the %-bound theophylline in foetal and maternal serum was performed using a paired t-test (n=5 pairs, * p<0.001).

Figure 3. Comparison of in vivo serum protein binding of theophylline

The extent of theophylline bound in vivo to serum protein was determined at 8–12 hr post-dose. Paired-comparisons of total (A) and free (B) theophylline concentrations between foetal and maternal serum were performed using paired t-tests (n=5 pairs, * p<0.01).

Figure 4. Foetal and maternal pharmacokinetic models of theophylline

Open three-compartment model for predicting theophylline concentration in foetal and ewe blood after IV bolus administration to the foetus. The compound is injected into the foetal central compartment (V₁), which represents the blood and very well-perfused foetal tissues. The foetal central compartment exchanges with peripheral compartments V₂, a shallow compartment potentially representing the placenta, and a deeper maternal compartment (V₃). Values for volumes and rates (Cl, Cl₂ and Cl₃) are provided in table 3.

Figure 5. Goodness-of-fit

Observed versus individual predicted values for the population model using foetal and ewe (A), and foetal and adjusted ewe (B) concentrations.