Pharmacokinetics of levonorgestrel and etonogestrel in rat or minipig following intravenous, subcutaneous, or intradermal administration

Figures & data

Figure 1. Levonorgestrel (LNG) concentration in Göttingen minipig following 30 µg via various routes of administration: intravenous (IV) bolus, IV infusion, and intradermal injection (semi-logarithmic scale). Points (i.e. shapes) represent individual observations and the lines (i.e. line types) represent the mean concentration. Any concentrations below the limit of quantitation were treated as zero values, thus affecting the overall mean concentration.

Figure 2. Levonorgestrel (LNG) concentration in Sprague-Dawley rat following 30 and 60 µg via various routes of administration: intravenous (IV) infusion, IV bolus, and subcutaneous (SC) (semi-logarithmic scale). Points (i.e. shapes) represent individual observations and the lines (i.e. line types) represent the mean concentration. Any concentrations below the limit of quantitation were treated as zero values, thus affecting the overall mean concentration.

Figure 3. Etonogestrel (ENG) concentration in Sprague-Dawley rat following 30 µg via intravenous (IV) bolus and IV infusion (semi-logarithmic scale). Points (i.e. shapes) represent individual observations and the lines (i.e. line types) represent the mean concentration. Any concentrations below the limit of quantitation were treated as zero values, thus affecting the overall mean concentration.

Table 1. Mean pharmacokinetic parameters following various routes of administration of LNG or ENG in rat and minipig.

Drug (Study #)	Species^a	Body Weight^b (kg)	Dose (µg)	Route	Cmax^b (ng/mL)	AUClast^b (ng·hr/mL)	AUCinf^b (ng·hr/mL)	t1/2^b (hr)	CL or CL/F^b (L/hr)	F
LNG (1)	Göttingen Minipig	11.5 ± 0.364	30	IV bolus	1.64 ± 0.476	1.35 ± 0.158	1.41 ± 0.143	5.44 ± 4.30	21.5 ± 2.08	–
		13.0 ± 0.418	30	IV infusion (24-hr)	0.0450 ± 0.00665	1.08 ± 0.398	–	–	–	–
		14.2 ± 0.466	30	Intradermal	0.313 ± 0.0908	1.32 ± 0.554	–	–	–	0.977
LNG (2)	Sprague-Dawley Rat	0.305 ± 0.0117	30	IV bolus	85.4	29.8	29.8	6.12	1.01	–
		0.286 ± 0.0253	30	IV infusion (24-hr)	0.947	20.7	20.7	1.00	1.45	–
LNG (3)	Sprague-Dawley Rat	0.247 ± 0.0227	60	IV infusion (1-hr)	42.4	60.8	60.9	1.64	0.985	–
		0.251 ± 0.0172	60	SC	36.5	55.0	55.0	2.52	1.09	0.903
ENG (4)	Sprague-Dawley rat	0.290 ± 0.0118	30	IV bolus	91.1	37.4	37.4	2.54	0.803	–
		0.271 ± 0.0112	30	IV infusion (24-hr)	1.47	31.0	31.0	4.12	0.968	–

#: number; LNG : levonorgestrel; ENG : etonogestrel; IV : intravenous; SC : subcutaneous; C_max: peak concentration following dose; AUC_last: area-under-the-curve to the last measurable timepoint; AUC_inf: area-under-the-curve extrapolated to infinity; t_1/2: half-life; CL or CL/F: (apparent) clearance; F : bioavailability; -: not applicable/not acceptable.

^aN : 4 for Göttingen minipig; N : 12 for Sprague-Dawley rat, mean data used for concentration-time profile.

^bArithmetic mean ± standard deviation (SD) when SD was reported.

Table 2. LNG and ENG PK following IV bolus in animal species from the previous studies^a.

Author(s) (Year)	Species (N)	Drug (Dose)	Body weight (kg)	Route (Formulation)	Assay	Cmax (ng/mL)	AUC (ng·hr/mL)	t1/2 (hr)	CL (L/hr/kg)
Düsterberg et al. (1981)	Wistar rat (N : 45)	LNG (10 µg)	0.14–0.16	IV bolus (dissolved in 1 mL saline)	RIA	N/R	N/R	0.5	N/R
	Beagle dog (N : 3)	LNG (100 µg)	12–14	IV bolus (dissolved in 10 mL saline)	RIA	N/R	N/R	1.2 ± 0.3	N/R
	Rhesus monkey (N : 3)	LNG (100 µg)	6–7	IV bolus (dissolved in 10 mL saline)	RIA	N/R	N/R	4.4 ± 0.5	N/R
Naqvi et al. (1984a)	Sprague-Dawley rat (N : 4)	LNG (8 µg)	0.25	IV bolus (dissolved in 40% ethyl alcohol)	RIA	N/R*	N/R*	N/R*	N/R*
Nair et al. (1981)	New Zealand White rabbit (N : 6)	LNG (15–20 µg/kg)	1.98 ± 0.227	IV bolus (carrier LNG in 0.4 mL of propylene glycol)	RIA	N/R*	N/R*	3.6 ± 0.83	N/R*
Düsterberg and Beier (1984)	Beagle dog (N : 6)	LNG (100 µg)	8–10	IV bolus (14 doses) (dissolved in 10 mL of saline:propylene glycol (1:1))	RIA	D1: 15.4 ± 2.8 D14: 12.9 ± 1.2	AUC0–24h D1: 21.2 ± 3.1 D14: 20.8 ± 0.7 AUC0–14d: 292	1.2 ± 0.3	D1: 0.534 ± 0.036 D14: 0.54 ± 0.048
Geelen et al. (1993)	Beagle dog (N : 4)	ENG (40–100 µg)	N/R	IV bolus (dissolved in mixtures of saline:propylene glycol (3:2))	HPLC-UV	N/R	N/R	2.0 ± 0.7	6.23 ± 1.87 L/hr

LNG : levonorgestrel; ENG : etonogestrel; IV : intravenous; N : number of animals per dose group; RIA : radioimmunoassay; HPLC-UV : high-performance liquid chromatography-ultraviolet; C_max: peak concentration following dose; AUC : area-under-the-curve exposure; t_1/2: half-life; CL : clearance; D1/D14 : Day 1/Day 14; N/R : not reported; N/R*: not reported but concentration-time profile available for digitisation and noncompartmental analysis.

^aArithmetic mean ± standard deviation (SD) when applicable.

Table 3. LNG and ENG PK following SC/IM/ID injection in animal species from the previous studies^a.

Author(s) (Year)	Species (N)	Drug (Dose)	Body weight (kg)	Administration	Assay	Cmax (ng/mL)	AUC (ng·hr/mL)	t1/2 (hr)	CL (L/hr)
Düsterberg (1984)	Wistar rat (N : 33–48)	LNG (1 mg)	0.14–0.16	SC (dissolved in 0.2 mL mixture (4:6) of benzyl benzoate:castor oil)	RIA	6,300 ± 200	N/R	N/R	N/R
	Beagle dog (N : 3)	LNG (1 mg)	12–14	SC (dissolved in 0.2 mL mixture (4:6) of benzyl benzoate:castor oil)	RIA	58 ± 20	N/R*	16 ± 3	N/R*
	Rhesus monkey (N : 3)	LNG (1 mg)	6–7	SC (dissolved in 0.2 mL mixture (4:6) of benzyl benzoate:castor oil)	RIA	246 ± 73	N/R*	N/R*	N/R*
Naqvi et al. (1984b)	Sprague-Dawley rat (N : 4)	LNG (8, 16, and 32 µg)	0.25	SC (dissolved in 0.2 mL of sesame oil)	RIA	8 µg: 4.51 ± 0.694	8 µg: 15.2 ± 1.48	8 µg: 2.42 ± 0.251	N/R
						16 µg: 6.33 ± 0.830	16 µg: 27.3 ± 3.44	16 µg: 3.01 ± 0.148
						32 µg: 10.2 ± 0.601	32 µg: 56.7 ± 9.52	32 µg: 3.80 ± 0.419
Ananthula et al. (2015)	Sprague-Dawley rat (N : 6)	LNG (4 mg/kg)	N/R	SC (4 mg in 400 µL NMP solution)	LC-MS/MS	229 ± 49.2	AUC0–48h: 889 ± 201	22.1 ± 4.97	16.4 ± 3.12
Düsterberg and Beier (1984)	Beagle dog (N : 6)	LNG (0.1 mg)	8–10	SC (14 doses) (dissolved in 0.2 mL mixture (4:6) of benzyl benzoate:castor oil)	RIA	D1: 0.53 ± 0.04	AUC0–24h D1: 10.4 ± 1.5 D14: 12.5 ± 2.1	N/R	N/R
						D14: 0.57 ± 0.15	AUC0–14d: 173
He et al. (2018)	Sprague-Dawley rat (N : 6)	ENG (700 µg)	0.18–0.22	IM and ID (ENG MPs suspended in HPMC solution)	UPLC-MS/MS	IM: 37.3 ± 8.1	IM: 425	N/R*	N/R*
						ID: 22.4 ± 7.6	ID: 399
He et al. (2020)	Sprague-Dawley rat (N : 6)	ENG (600 µg)	0.18–0.22	SC (PLGA and ENG dissolved in NMP at a ratio of 6:4)	UPLC-MS/MS	41.0 ± 11.6	AUCinf: 463.2	N/R*	N/R*

LNG : levonorgestrel; ENG : etonogestrel; SC : subcutaneous; IM : intramuscular; ID : intradermal; N : number of animals per dose group; NMP : N-methyl-2-pyrrolidone; MP : microcrystal particles; HPMC : hydroxypropyl methylcellulose; PLGA : poly(lactic-co-glycolic acid); RIA : radioimmunoassay; LC-MS/MS : liquid chromatography-tandem mass spectrometry; UPLC-MS/MS : ultra-performance liquid chromatography-tandem mass spectrometry; C_max: peak concentration following dose; AUC : area-under-the-curve exposure; t_1/2: half-life; CL : clearance; D1/D14 : Day 1/Day 14; N/R : not reported; N/R*: not reported but concentration-time profile available for digitisation and noncompartmental analysis.

^aArithmetic mean ± standard deviation (SD) when applicable.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within its supplementary materials.