TABLE 2.

Pharmacokinetic parameters derived from the plasma d₃- and d₆-α-T concentrations following oral d₃- and IV d₆-α-T administration during 3 interventions¹

Parameter	DLM interventions	IV d6-α-T	Compared with 0% fat,2P value	Oral d3-α-T	Compared with 0% fat,3P value	Oral d3- compared with IV d6-α-T per intervention,4P value	Overall interaction,5P value
Elimination rate, Ke	40% fat	0.022 ± 0.001	0.1801	0.024 ± 0.002	0.6961	0.1242	0.0500*
	0% fat	0.020 ± 0.001		0.023 ± 0.002		0.0867
	0% fat-fast	0.024 ± 0.001	0.0034*	0.022 ± 0.002	0.6701	0.1197
Half-life, h	40% fat	32.7 ± 1.4	0.0973	30.0 ± 2.1	0.6784	0.0994	0.0075*
	0% fat	34.6 ± 1.4		31.2 ± 2.0		0.0512
	0% fat-fast	30.3 ± 1.5	0.0019*	32.5 ± 2.6	0.6939	0.0217*
Cmax, μmol/L	40% fat	7.1 ± 0.6	0.8734	4.1 ± 0.4	0.3149	<0.0001*	0.0483*
	0% fat	6.9 ± 0.6		4.7 ± 0.4		<0.0001*
	0% fat-fast	7.4 ± 0.7	0.6520	3.6 ± 0.5	0.0927	<0.0001*
Tmax,6 h	40% fat	8.0 ± 0.6	0.2513	12.4 ± 1.5	0.9374	0.0177*	0.0565
	0% fat	7.1 ± 0.5		12.3 ± 1.5		0.0069*
	0% fat-fast	8.7 ± 0.6	0.0677	19.5 ± 1.8	0.0041*	<0.0001*
AUC0–72,7 μmol · h/L	40% fat	272 ± 25	0.9873	147 ± 17	0.2130	<0.0001*	0.3414
	0% fat	273 ± 25		176 ± 17		<0.0001*
	0% fat-fast	253 ± 30	0.6217	139 ± 20	0.1551	<0.0001*
Fractional absorption (0–72 h)8	40% fat			55% ± 3%	0.0212*
	0% fat			64% ± 3%
	0% fat-fast			56% ± 3%	0.0670

¹Pharmacokinetic (PK) parameters (mean ± SEM) were calculated from the d₆-α-T and d₃-α-T concentrations as described in Methods from data shown in Figure 3A–C from women in the following interventions: 40% fat, n = 10; 0% fat, n = 10; and 0% fat, fasting 12 h, n = 7. *Statistically significant values. Cmax, maximum concentration; DLM, defined liquid meal; K _e, post-Cmax elimination rate; IV, intravenous; Tmax, time of Cmax. The statistical analysis was carried out to answer the questions in the footnotes shown below.

²What is the effect of the intervention on the IV d₆-α-T dose PK parameter? Pharmacokinetic parameters derived from d₆-α-T concentrations were analyzed as an incomplete crossover design in SAS PROC MIXED with treatment (40% fat, 0% fat, and 0% fat-fast) as fixed effect and subject as random effect. Using the ESTIMATE statements, the effect of DLM fat was evaluated using the contrast between 40% fat and 0% fat interventions, while the effect of fasting was evaluated using the contrast between 0% fat and 0% fat-fast interventions.

³What is the effect of the intervention on the oral d₃-α-T dose PK parameter? Pharmacokinetic parameters derived from d₃-α-T concentrations were analyzed as an incomplete crossover design in SAS PROC MIXED with treatment (40% fat, 0% fat, and 0% fat-fast) as fixed effect and subject as random effect. Using the ESTIMATE statements, the effect of DLM fat was evaluated using the contrast between 40% fat and 0% fat interventions, while the effect of fasting was evaluated using the contrast between 0% fat and 0% fat-fast interventions.

⁴Are there differences in the IV compared with oral α-T responses for each PK parameter? For comparisons between d₆-α-T and d₃-α-T pharmacokinetic parameters, the differences between d₆-α-T and d₃-α-T for each parameter were calculated, and then the data were analyzed as a crossover design in SAS PROC MIXED with treatment (40% fat, 0% fat, 0% fat-fast) as fixed effect and subject as random effect.

⁵Did the response differ between the intervention and the route (IV d₆-α-T and oral d₃-α-T) for the PK parameter? To determine whether the effect of the route of α-T administration differed across treatments, the overall interaction was analyzed as a Latin square design with double repeated measures (Kronecker product) in SAS PROC MIXED. Fixed effects were interventions (40% fat, 0% fat, 0% fat-fast), the route of α-T administration (oral, IV) and their interaction. The variance–covariance structure within subjects was modeled by using a Kronecker product, in which the intervention was modeled using a compound symmetry matrix and the type of treatment within treatment was modeled using an unstructured variance–covariance matrix.

⁶Tmax is postnadir for the IV dose.

⁷AUC_0–72 is calculated from the plasma concentrations from 0 to 72 h.

⁸From the dual-isotope method (% absorption = oral AUC_0–72/IV AUC_0–72 × 100).