. 2018 Nov 13;219(9):1464–1473. doi: 10.1093/infdis/jiy664

Table 2.

Modeled Pharmacokinetic Data and Efficacy Against Acute Toxoplasmosis in Mice

		Administered Oral Dose	Simulated AUC	Simulated C_avg	Simulated fu C_avg	Simulated C_max	Simulated fu C_max	Simulated Fraction of Time Above EC₅₀		Simulated Fraction of Time Above EC₉₀		Reduction Over Controls for Peritoneal Infection for Type I RH Strain	Reduction Over Controls for Brain Infection for Type I RH Strain	Reduction Over Controls for Spleen Infection for Type I RH Strain	Reduction Over Controls for Brain Infection for Type II Prugniaud strain
Central Scaffold	BKI	(starting on Day 2 postinfection)	(µM*h)	(µM)	(µM)	(µM)	(µM)	Total	fu	Total	fu	(%)	(%)	(%)	(%)
PP	1553^a	2 mg/kg QD × 5 days	408	1.2	0.1	4.3	0.4	0.81	0.57	0.38	0	71	34	46	ND
		10 mg/kg × 1 dose	408	1.2	0.1	12.3	1.2	0.80	0.37	0.29	0	65	57	41	ND
		20 mg/kg loading dose on day 2 + 5 mg/kg QD on days 3–6	1630	4.9	0.5	24.6	2.5	0.74	0.55	0.44	0.03	99.9	79	97	ND
		20 mg/kg QD × 5 days	4076	12.1	1.2	43.0	4.3	0.85	0.66	0.55	0.30	100^c	95	99	ND
PP	1561^a	2 mg/kg QD × 5 days	319	1.5	0.2	3.8	0.5	0.68	0.51	0.40	0	80	95	97	ND
		10 mg/kg QD × 1 dose	319	1.5	0.2	15.2	1.8	0.78	0.45	0.40	0	97	99	99	ND
		20 mg/kg loading dose on day 2 + 5 mg/kg QD on days 3–6	1276	5.8	0.7	30.4	4.9	0.84	0.70	0.65	0.16	100^c	99	98	ND
PrP	1660	2 mg/kg QD × 5 days	726	3.0	0.03	7.6	0.1	0.72	0	0.34	0	48	69	ND	ND
		10 mg/kg × 3 doses QOD on days 2, 4, and 6	2179	8.9	0.1	28.0	0.3	0.63	0.02	0.43	0	97	76	ND	ND
		10 mg/kg QD × 5 days	3630	14.9	0.2	37.6	0.4	0.87	0.23	0.62	0	96	85	ND	88
		30 mg/kg QD × 1 day	2179	13.0	0.1	74.7	0.8	0.78	0.18	0.41	0	66	41	ND	ND
PrP	1649	2 mg/kg QD × 5 days	514	2.3	0.1	5.8	0.3	0.82	0.58	0.60	0	99.8	85	ND	ND
		6 mg/kg QD × 5 days	1541	7.0	0.4	17.5	1.0	0.97	0.70	0.72	0	100^c	97	ND	ND
		10 mg/kg QD × 5 days	2771	12.6	0.8	30.1	1.8	0.95	0.73	0.74	0.33	ND	ND	ND	99
PrP	1812	20 mg/kg QD × 5 days	452	3.6	0.5	22.2	3.3	0.61	0.41	0.47	0.28	ND	ND	ND	97
AC	1673	2 mg/kg QD × 5 days	166	1.0	0.05	2.7	0.2	0.80	0.11	0.29	0	81	72	ND	ND
		5 mg/kg QD × 5 days	414	2.4	0.1	7.2	0.4	0.77	0.46	0.60	0	97	86	ND	ND
		10 mg/kg QD × 5 days	829	4.8	0.2	14.3	0.8	0.80	0.61	0.65	0	99.7	92	ND	ND
		20 mg/kg QD × 5 days	1658	9.6	0.5	28.7	1.5	0.84	0.67	0.69	0.01	100^c	97	ND	97
AC	1643^b	20 mg/kg QD × 5 days	219	1.1	0.1	3.7	0.5	0.79	0.64	0.63	0.0	100^c	89	100^c	ND
		50 mg/kg QD × 5 days	546	2.7	0.3	9.3	1.1	0.86	0.71	0.62	0.07	100^c	88	100^c	ND
AC	1597	4 mg/kg QD × 5 days	51	0.4	0.1	1.9	0.4	0.49	0.15	0.15	0.00	87	91	ND	ND
		20 mg/kg QD × 5 days	282	2.2	0.3	10.5	2.1	0.84	0.49	0.48	0.15	99.9	98	ND	99
		60 mg/kg QD × 5 days	764	6.0	0.7	28.5	4.6	0.89	0.76	0.75	0.29	100^c	97	ND	ND
AC	1748	4 mg/kg QD × 5 days	540	3.9	0.8	17.0	3.5	0.90	0.86	0.84	0.51	95	79	98	ND
		20 mg/kg QD × 5 days	2700	19.6	3.9	86.7	17.4	0.92	0.87	0.87	0.80	100^c	86	100^c	99
AC	1757	4 mg/kg QD × 5 days	382	2.3	0.3	6.8	0.7	0.76	0.73	0.67	0	72	34	65	ND
		20 mg/kg QD × 5 days	1908	11.4	1.4	33.6	3.7	0.86	0.77	0.76	0.55	98	79	99	99

Abbreviations: AC, 5-aminopyrazole-4-carboxamides; AUC, area under the curve; BKI, bumped kinase inhibitor; C_avg, average concentration over dosing time; C_max, maximum concentration; EC₅₀, 50% effective concentration; EC₉₀, 90% effective concentration; fu, fraction unbound; ND, not determined; PP, pyrazolopyrimidines; PrP, pyrrolopyrimidines; QD, once daily; QOD, once every other day.

^aBKIs and some associated data previously reported [11] as compounds 32, and 33.

^bBKI and some associated data previously reported [13] as compound 35.

^cValues below the assay’s lowest limit of detection are reported as 100% reduction.