tiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3).
Table 3: Summary of NGMN, NG and EE pharmacokinetic parameters. 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, NC = not calculated.
NGMN and NG: Cmax = ng/mL, AUC0–24h = h∙ng/mL
EE: Cmax = pg/mL, AUC0–24h = h∙pg/mL
Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0–24h t1/2 (h)
NGMN 3 7 1.80 (0.46) 1.42 (0.73) 15.0 (3.88) NC
14 2.12 (0.56) 1.21 (0.26) 16.1 (4.97) NC
21 2.66 (0.47) 1.29 (0.26) 21.4 (3.46) 22.3 (6.54)
NG 3 7 1.94 (0.82) 3.15 (4.05) 34.8 (16.5) NC
14 3.00 (1.04) 2.21 (2.03) 55.2 (23.5) NC
21 3.66 (1.15) 2.58 (2.97) 69.3 (23.8) 40.2 (15.4)
EE 3 7 124 (39.5) 1.27 (0.26) 1130 (420) NC
14 128 (38.4) 1.32 (0.25) 1130 (324) NC
21 126 (34.7) 1.31 (0.56) 1090 (359) 15.9 (4.39)
Mean (SD) Pharmacokinetic Parameters of ORTHO-CYCLEN During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0–24h t1/2 (h)
NGMN 1 1 1.78 (0.397) 1.19 (0.250) 9.90 (3.25) 18.4 (5.91)
3 21 2.19 (0.655) 1.43 (0.680) 18.1 (5.53) 24.9 (9.04)
NG 1 1 0.649 (0.49) 1.42 (0.69) 6.22 (2.46) 37.8 (14.0)
3 21 2.65 (1.11) 1.67 (1.32) 48.2 (20.5) 45.0 (20.4)
EE 1 1 92.2 (24.5) 1.2 (0.26) 629 (138) 10.1 (1.90)
3 21 147 (41.5) 1.13 (0.23) 1210 (294) 15.0 (2.36)
Food Effect
The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN 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 (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.
Excretion
The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45–49%) and 37% (16–49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in
