Tri-Lo-Sprintec (Page 5 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Tri-Lo-Sprintec.

12.3 Pharmacokinetics

Absorption

Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of NGM.

Mean pharmacokinetic parameters for NGMN, NG and EE during three cycles of administration of Tri-Lo-Sprintec are summarized in Table 3.

Peak serum concentrations of NGMN and EE were generally reached by 2 hours after administration of Tri-Lo-Sprintec. Accumulation following multiple dosing of the 0.180 mg NGM / 0.025 mg EE dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for EE compared with single dose administration, in agreement with that predicted based on linear kinetics of NGMN and EE. The pharmacokinetics of NGMN is dose proportional following NGM doses of 0.180 to 0.250 mg. Steady-state conditions for NGMN following each NGM dose and for EE were achieved during the three cycle study. Non-linear accumulation (4.5 to 14.5 fold) of NG was observed as a result of high affinity binding to SHBG, which limits its biological activity.

Table 3 Summary of NGMN, NG and EE pharmacokinetic parameters.

Table 3: Mean (SD) Pharmacokinetic Parameters of Tri-Lo-Sprintec During a Three Cycle Study

* NGMN = Norelgestromin, NG = norgestrel, EE = ethinyl estradiol † Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area under serum concentration vs. time curve from 0 to 24 hours, t1/2 = elimination half-life. ‡ units for NGMN and NG – Cmax = ng/mL, AUC0-24h = h•ng/mL § units for all analytes; h = hours ¶ units for EE only – Cmax = pg/mL, AUC0-24h = h•pg/mL
Analyte *	Cycle	Day	Cmax	tmax (h)	AUC0-24h	t1/2 (h)
NGMN( † – ‡ )	1	1	0.91 (0.27)	1.8 (1.0)	5.86 (1.54)	NC
	3	7	1.42 (0.43)	1.8 (0.7)	11.3 (3.2)	NC
		14	1.57 (0.39)	1.8 (0.7)	13.9 (3.7)	NC
		21	1.82 (0.54)	1.5 (0.7)	16.1 (4.8)	28.1 (10.6)
NG( † – ‡ )	1	1	0.32 (0.14)	2.0 (1.1)	2.44 (2.04)	NC
	3	7	1.64 (0.89)	1.9 (0.9)	27.9 (18.1)	NC
		14	2.11 (1.13)	4.0 (6.3)	40.7 (24.8)	NC
		21	2.79 (1.42)	1.7 (1.2)	49.9 (27.6)	36.4 (10.2)
EE( † , § , ¶ )	1	1	55.6 (18.1)	1.7 (0.5)	421 (118)	NC
	3	7	91.1 (36.7)	1.3 (0.3)	782 (329)	NC
		14	96.9 (38.5)	1.3 (0.3)	796 (273)	NC
		21	95.9 (38.9)	1.3 (0.6)	771 (303)	17.7 (4.4)

NC = not calculated

Food Effect

The effect of food on the pharmacokinetics of Tri-Lo-Sprintec has not been studied.

Distribution

NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.

Metabolism

NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM’s primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (K_i ). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

Following 3 cycles of administration of Tri-Lo-Sprintec, the mean (± SD) elimination half-life values, at steady-state, for NGMN, NG and EE were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (Table 2). The metabolites of NGMN and EE are eliminated by renal and fecal pathways.

Use in Specific Populations

Effects of Body Weight, Body Surface Area, and Age

The effects of body weight, body surface area, age and race on the pharmacokinetics of NGMN, NG and EE were evaluated in 79 healthy women using pooled data following single dose administration of NGM 0.180 or 0.250 mg / EE 0.025 mg tablets in four pharmacokinetic studies. Increasing body weight and body surface area were each associated with decreases in C_max and AUC_0-24h values for NGMN and EE and increases in CL/F (oral clearance) for EE. Increasing body weight by 10 kg is predicted to reduce the following parameters: NGMN C_max by 9% and AUC_0-24h by 19%, NG C_max by 12% and AUC_0-24h by 46%, EE C_max by 13% and AUC_0-24h by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in C_max and AUC_0-24h for NGMN and were statistically significant, but there was no significant effect for NG or EE. Only a small to moderate fraction (5 to 40%) of the overall variability in the pharmacokinetics of NGMN and EE following Tri-Lo-Sprintec tablets may be explained by any or all of the above demographic parameters.