TABLE 1

Drug parameters relevant for clinical extrapolation of in vitro transport inhibition

Drug	Mol. Wt.	Dose	C_max	f_u	C_max,u	I_gut	Reference
	g/mol	mg	µM		µM	µM
Dolutegravir	441.36	50	8.32^{^a}	0.01	0.08^{^a}	453.14	Tivicay, Prescribing Information, 2018
Cabotegravir	427.33	30	14.88	0.01	0.15	280.81	Ford et al., 2019
Bictegravir	449.38	50	13.69	0.01	0.14	445.06	Biktarvy, Prescribing Information, 2018
Raltegravir	482.51	400	4.50	0.17	0.76	3315.99	Isentress (raltegravir) Prescribing Information, 2019
Raltegravir	482.51	1200	22.56	0.17	3.84	9947.98	http://wwwcroiconferenceorg/sessions/multiple-dose-study-raltegravir-ral-formulations
Elvitegravir	447.88	85	2.68^{^b}	0.02	0.05^{^b}	759.13	Viteka Prescribing Information, 2015
Elvitegravir	447.88	150	3.35^{^b}	0.02	0.07^{^b}	1339.64	Viteka Prescribing Information, 2015
Methotrexate	454.44	10	0.57	0.5	0.28	88.02	Jylamvo (methotrexate) Prescribing Information, 2017
Methotrexate (i.v.)	454.44	15	3.80	0.5	1.90	N/A	Seideman et al., 1993
Pemetrexed (i.v.)	597.49	500 mg/m²	189.12	0.19	35.93	N/A	Kavathiya et al., 2017

C_max,u, unbound C_max (i.e., C_max * f_u); f_u, plasma fraction unbound; I_gut, theoretical gut concentration (oral dose/250 ml) or highest soluble aqueous concentration; oral administration in all cases, unless noted); N/A, not applicable (i.v. administration).
↵^a Most commonly used 50-mg daily regimen; 50 mg twice daily; C_max = 9.4 μM and C_max,u = 0.09 μM (ViiV Healthcare, 2018), twice-daily dosing does not impact extrapolation values or results in Fig. 6.
↵^b Not cobicistat boosted, 150-mg dose cobicistat-boosted C_max = 3.8 μM and C_max,u = 0.08 μM (2019); cobicistat boosting does not impact extrapolation values or results in Fig. 6.