Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers

Figures & data

Figure 1 Study design.

Notes: End of pharmacokinetic sampling occurred at days 7 and 21. End of study evaluation was performed 14 (±2) days after everolimus administration in the second time period.
Abbreviation: R, randomization.

Table 1 Baseline characteristics

	Everolimus 1×5 mg → 5×1 mg n=11	Everolimus 5×1 mg → 1×5 mg n=11	All participants N=22
Age, years*	50.0 (25–63)	40.0 (27–65)	47.5 (25–65)
Sex, n (%)
Women	9 (82)	7 (64)	16 (73)
Men	2 (18)	4 (36)	6 (27)
Race, n (%)
Caucasian	11 (100)	11 (100)	22 (100)
BMI, kg/m^2*	23.8 (20.5–28.4)	25.7 (22.3–29.7)	24.5 (20.5–29.7)

Notes: BMI was calculated using baseline values for weight and height.

* Values are expressed as median (range).

Abbreviation: BMI, body mass index.

Figure 2 Arithmetic mean (SD) blood concentration–time profiles from 0 to 4 hours for everolimus administered as five 1 mg tablets and as one 5 mg tablet (PK population, N=22).

Abbreviations: PK, pharmacokinetics; SD, standard deviation.

Table 2 Relative bioavailability of everolimus one 5 mg tablet versus five 1 mg tablets (PK population, N=22)

PK parameter	Everolimus dose	Adjusted geometric mean	Treatment comparisona
			Geometric mean ratio	90% CI
AUCinf (ng · h/mL)	1×5 mg 5×1 mg	243 264	1.08	1.02–1.16
Cmax (ng/mL)	1×5 mg 5×1 mg	28.7 42.3	1.48	1.35–1.62

Notes:

a Comparison of everolimus five 1 mg tablets (test) with one 5 mg tablet (reference).

Abbreviations: AUC, area under the concentration–time curve; AUCinf, AUC from time zero to infinity; Cmax, maximum blood concentration; CI, confidence interval; PK, pharmacokinetics.

Figure 3 Arithmetic mean (SD) blood concentration–time profiles for everolimus administered as five 1 mg tablets and as one 5 mg tablet (PK population, N=22).

Abbreviations: PK, pharmacokinetics; SD, standard deviation.

Table 3 Summary of secondary PK parameters of everolimus by treatment (PK population, N=22)

Everolimus treatment	Statistics	AUCall (ng · h/mL)	AUC0–144h (ng · h/mL)	Tmax (h)	Lambda_z (1/h)	CL/F (L/h)	T1/2 (h)
1×5 mg	Mean (SD)	238 (60.7)	238 (60.5)	N/A	0.0227 (0.00366)	21.2 (5.19)	31.2 (4.79)
	CV% mean	25.5	25.5	N/A	16.1	24.5	15.4
	Geometric mean	231	230	N/A	0.0225	20.6	30.9
	CV% geometric mean	25.5	25.4	N/A	15.7	25.0	15.7
	Median	219	218	1.01	0.0224	21.7	31.0
	Min, max	142, 375	142, 373	0.500, 2.48	0.0163, 0.0331	12.9, 33.7	21.0, 42.6
5×1 mg	Mean (SD)	260 (75.5)	260 (75.3)	N/A	0.0228 (0.00351)	19.7 (5.79)	31.1 (4.84)
	CV% mean	29.0	29.0	N/A	15.4	29.4	15.6
	Geometric mean	250	250	N/A	0.0225	19.0	30.7
	CV% geometric mean	30.2	30.1	N/A	15.6	29.0	15.6
	Median	263	263	0.500	0.0226	18.3	30.7
	Min, max	135, 450	135, 449	0.500, 1.02	0.0173, 0.0289	10.7, 34.7	24.0, 40.0

Notes: For Tmax, only median and range are presented. CV% = SD/mean ×100. CV% geometric mean = sqrt (exp [variance for log-transformed data] − 1) ×100.

Abbreviations: AUC0–144h, area under the concentration–time curve from time zero to the 144-hour concentration sampling time; AUCall, area under the concentration– time curve from time zero to time of last observation time point, regardless of whether the last concentration is quantifiable; CL/F, systemic clearance; CV%, coefficient of variation (%); Lambda_z, terminal slope of elimination phase; N/A, not applicable; PK, pharmacokinetics; SD, standard deviation; sqrt, square root; T1/2, terminal half-life; Tmax, time taken to reach maximum blood concentration; min, minimum; max, maximum.

Table 4 Number of subjects who experienced adverse events, regardless of study drug relationship (safety population, N=22)

Adverse event, n (%)	All subjects (N=22)
Total	12 (54.5)
Headache	6 (27.3)
Dry skin	2 (9.1)
Myalgia	2 (9.1)
Nasopharyngitis	2 (9.1)
Nausea	2 (9.1)
Diarrhea	1 (4.5)
Dizziness	1 (4.5)
Erythema	1 (4.5)
Oral herpes	1 (4.5)
Phlebitis	1 (4.5)
Rhinitis	1 (4.5)
Vaginal hemorrhage	1 (4.5)
Vomiting	1 (4.5)

Note: All adverse events were grade 1 or 2.