TABLE 2.

Key aspects of PKPD studies.

Study	Study design	TB	Participants	PK	PD	Application
In vitro	Intracellular	H37Ra H37Rv Clinical isolates	cells	Sampling of system (multiple)	CFU	*Define PKPD parameters for optimal kill, prevention of resistance
	Extracellular
In vivo	Balb/c		animals	1 sample/animal, different time points different animals	CFU	*Define PKPD parameters for cure, prevention of resistance, relapse
	C3Heb/Fej
EBA	Selected TB patients with drug susceptible TB	Clinical isolates	patients	Full PK curve	CFU, TTP	Confirm activity in humans, confirm PKPD relationship, define dose for phase 2b
					Daily for 14 days
Phase 2/3	Selected TB patients with drug susceptible or drug resistant TB	Clinical isolates	patients	Limited samples in all participants, Full PK curve in subset of the patients	Culture conversion, treatment outcome	Define dose for regulatory approval
TDM	Clinical practice	Clinical isolates	patients	Ranging van limited samples to full PK curve	Successful treatment of individual patients	Define subpopulations, situations where standard dose is likely not effective or toxic

TB, tuberculosis; PK, pharmacokinetics; PD, pharmacodynamics; CFU, colony forming units; TTP, time to positivity; TDM, therapeutic drug monitoring; *The MIC of the strain used in the in vitro/in vivo study should be determined before each experiment as well as the MIC of the clinical strains to determine if the given clinical dose could achieve the PK/PD exposure target in patients.