Figure 1.

Schematic describing the final model. The dose (DOSE) is transferred from the absorption site (Abs) to the central compartment by a transit rate constant k_tr, which is described by the number of compartments (n) +1 divided by the mean transit time (MTT). Drug is eliminated linearly as described by rifampicin oral clearance (CL/F) divided by the apparent volume of distribution (V/F), at the preinduced stage. The pharmacokinetic (PK) model includes an enzyme turnover model, in which plasma concentrations of rifampicin (C_RIF) increase the rate constant for first‐order degradation of the enzyme pool (k_ENZ), which leads to an increase in the enzyme pool (ENZ) with an E_max model leading to increased elimination of rifampicin. The parameter EC₅₀ is the rifampicin concentration (C_RIF) at which half the E_max is reached. E_max is the maximal increase in the enzyme production rate. C_RIF drives the effect implemented in the Multistate Tuberculosis Pharmacometric (MTP) model. The MTP model consists of three bacterial compartments; the fast‐multiplying state (F), the slow‐multiplying state (S), and the nonmultiplying state (N). Growth is present for F described by a fast‐multiplying bacterial growth rate (k_G) multiplied by the natural logarithm of the system carrying capacity per milliliter sputum (B_max) divided by the number of F, S, and N. F can transfer to N described by the transfer rate from fast‐ to nonmultiplying state (k_FN). Transfer between F and S is described by a time‐dependent transfer rate from fast‐ to slow‐multiplying state (k_FSlin). S can transfer to F and N described by the transfer rate from slow‐ to fast‐multiplying state (k_SF) and transfer rate from slow‐ to nonmultiplying state (k_SN), respectively. N can transfer to S described by the transfer rate from non‐ to slow‐multiplying state (k_NS). Drug effect enters the model as fractional inhibition of growth of fast‐multiplying state (FG_on/off) in presence of drug according to the PK model, as second‐order nonmultiplying death rate (ND_k) and as second‐order slow‐multiplying death rate (SD_k). The bacterial number of F and S together with the sputum production rate (k_prod) describes the amount of bacteria that is present in the sputum sample compartment (Sample).