Table 1.
Overview of population pharmacokinetic models of anti-tuberculosis drugs
| First author, year | Software | Covariate–parameter relationships | Population, country of origin (n) | Model structure |
|---|---|---|---|---|
| Isoniazid | ||||
| Peloquin, 1997 [25] | NPEM2, IT2B | – | Healthy male adults (24), USA | No model specified, NPEM and IT2B analysis |
| Wilkins, 2011 [174] | NONMEM |
Sex, V HIV, CL Acetylation status, CL Body weight, CL Body weight, V |
Patients with TB, adults (235), South Africa |
Two-compartment, first-order absorption and elimination with allometric scaling |
| Zvada, 2014 [175] | NONMEM |
NAT2 genotype, CL NAT2 genotype, F Body weight, CL Body weight, V |
Patients with TB, children (76), South Africa | Two-compartment, first-order elimination, distribution with absorption transit compartments |
| Hiruy, 2015 [181] | ADAPT5 | – | Patients with TB (children 31), South Africa | Two-compartment |
| Seng, 2015 [182] | NONMEM |
NAT2 genotype, CL Body weight, CL Body weight, V |
Healthy adults (33), Singapore | Two-compartment, first-order absorption |
| Denti, 2015 [76] | NONMEM |
Acetylation status, CL Body weight, CL Fat-free mass, V |
Patients with TB, adults (100), Tanzania | Two-compartment disposition, transit compartment absorption |
| Lalande, 2015 [183] | Pmetrics | Acetylation status, Ke | Adults with and without AIDS, volunteers without TB (89) | Three-compartment |
| Rockwood, 2016 [184] | Monolix |
HIV, CL NAT2 genotype, CL |
Patients with TB/HIV (100), South Africa | Two-compartment, first-order elimination and absorption through transit compartments |
| Vinnard, 2017 [185] | NONMEM | NAT2 genotype, CL | Patients with TB (40), Botswana | Two-compartment, first-order elimination |
| Horita, 2018 [30] | Monolix | NAT2 genotype, CL | Patients with TB, children (113), Ghana | Two-compartment, first-order absorption and linear elimination |
| Chirehwa, 2019 [186] | NONMEM |
Acetylation status, CL Fat-free mass, CL Fat-free mass, V |
Patients with TB/HIV, adults (150), Benin and Guinea | Two-compartment disposition, lag time in absorption, liver compartment |
| Aruldhas, 2019 [187] | NONMEM |
Body weight, CL Body weight, V Acetylation status, CL |
Patients with TB, children (41), India | One-compartment disposition, absorption phase with transit compartments |
| Rifampicin | ||||
| Peloquin, 1997 [25] | NPEM2, IT2B | – | Healthy male adults (24), USA | |
| Wilkins, 2008 [176] | NONMEM |
FDC/SDF, CL FDC/SDF, MTT |
Patients with pulmonary TB (261), South Africa | One-compartment, transit compartment |
| Goutelle, 2009 [188] | NONMEM | – | Patients with HIV (20) and healthy volunteers (20), USA | Three-compartment |
| Smythe, 2012 [189] | NONMEM |
Normal fat mass, CL Normal fat mass, V HIV, V |
Patients with pulmonary TB (174), Africa | One-compartment, transit compartment, auto-induction |
| Milán-Segovia, 2013 [190] | NONMEM |
Sex, CL Sex, V |
Patients with TB (171), Mexico | One-compartment, lag time |
| Hiruy, 2015 [181] | ADAPT5 | – | Patients with TB (children 31), South Africa | One-compartment |
| Jeremiah, 2014 [191] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Patients with TB/HIV (100), Tanzania | One-compartment, first-order absorption, transit compartment absorption |
| Seng, 2015 [192] | NONMEM |
Body weight, CL Body weight, V |
Healthy adults (34), Asia | One-compartment, transit compartment |
| Sturkenboom, 2015 [14] | MWPharm | – | Patients with TB (55), the Netherlands | One-compartment |
| Jing, 2015 [193] | NONMEM | – | Patients with pulmonary TB (54), China | One-compartment |
| Savic, 2015 [15] | NONMEM |
Body weight, CL Body weight, V |
Patients with TB meningitis (children, 53), Indonesia | Two-compartment |
| Denti, 2015 [194] | NONMEM |
Body weight, CL Body weight, V |
Pregnant women with TB/HIV (48), South Africa | One-compartment, first-order elimination, transit compartment absorption |
| Schipani, 2016 [195] | NONMEM |
Age, F Age, CL Body weight, CL Body weight, V |
Patients with TB, adults (115) and children (50), Malawi | One-compartment |
| Chirehwa, 2016 [39] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Patients with TB/HIV (61), South Africa | One-compartment, transit compartment, auto-induction |
| Rockwood, 2016 [184] | Monolix |
HIV, CL lopinavir/ritonavir based antiretroviral regimen, CL |
Patients with TB/HIV (100), South Africa | One-compartment, first-order elimination and first-order absorption, with an absorption lag time |
| Svensson, 2017 [46] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Patients with pulmonary TB (83), South Africa | One-compartment, transit compartment, auto-induction |
| Horita, 2018 [30] | Monolix | – | Patients with TB, children (113), Ghana | One-compartment, sequential zero- and first-order absorption, first-order elimination |
| Svensson, 2018 [44] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Patients with TB (336), Tanzania and South Africa | One distribution compartment, absorption through a dynamic transit compartment, Michelis–Menten function limiting the clearance at high concentrations |
| Svensson, 2019 [38] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Adult patients with TB (133), Indonesia | Two disposition compartments, saturable clearance, and autoinduction |
| Pyrazinamide | ||||
| Zhu, 2002 [196] |
PASTRX, NPEM2, USC*PACK |
– | Adult patients with TB (67), children (23), USA | No model specified, NPEM analysis |
| Hiruy, 2015 [181] | ADAPT5 | – | Patients with TB (children 31), South Africa | One-compartment |
| Denti, 2015 [76] | NONMEM |
Fat-free mass, CL Fat-free mass, V NAT2 acetylation status, CL |
Patients with TB, adults (100), Tanzania | One-compartment, first-order elimination, One-compartment, first-order elimination, transit compartment absorption |
| Rockwood, 2016 [184] | Monolix | – | Patients with TB/HIV (100), South Africa | One-compartment, first-order elimination, transit compartment absorption |
| Vinnard, 2017 [65] | NONMEM |
Sex, CL Body weight, CL Body weight, V |
Patients with TB/HIV (40), Botswana | One-compartment, first-order elimination |
| Chirehwa, 2017 [58] | NONMEM | – | Patients with TB/HIV (61), South Africa | One-compartment, first-order elimination, transit compartment absorption |
| Horita, 2018 [30] | Monolix | – | Patients with TB, children (113), Ghana | One-compartment, with transit compartment absorption and first-order elimination |
| Mugabo, 2019 [197] | Monolix | – | Patients with MDR-TB (51), South Africa | One-compartment, transit compartment absorption process and first-order elimination |
| Abdelwahab, 2020 [79] | NONMEM |
Body size, CL Body size, V |
Pregnant women with TB/HIV (29), South Africa | One-compartment disposition, first-order elimination and transit compartment absorption |
| Ethambutol | ||||
| Peloquin, 1999 [72] | ADAPTII | Adult healthy volunteers (14) | Two-compartment, lag time | |
| Zhu, 2004 [73] | NPEM2 | Serum creatinine, half life | Patients with TB, adults (56) and children (14), USA | One-compartment |
| Jönsson, 2011 [74] | NONMEM |
HIV, F Body weight, CL Body weight, V |
Patients with TB, adults (189), South Africa | Two-compartment, transit compartment absorption |
| Hall, 2012 [75] | ADAPT5 | Weight, CL | Adults, healthy volunteers (18) | Two-compartment |
| Hiruy, 2015 [181] | ADAPT5 | – | Patients with TB (children 31), South Africa | One-compartment |
| Denti, 2015 [76] | NONMEM |
Age, CL Fat-free mass, CL Fat-free mass, V |
Patients with TB, adults (98), Tanzania | Two-compartment, transit compartment absorption |
| Horita, 2018 [30] | NONMEM |
HIV, V1/F Body weight, CL Body weight, V |
Patients with TB, children (113), Ghana | Two-compartment, lag time |
| Mehta, 2019 [77] | Phoenix NLME | ART initiation, F | Adults with co-infected TB/HIV (40), Botswana | Two-compartment, lag time |
| Sundell, 2020 [78] | NONMEM |
CYP1A2, F Body weight, CL Body weight, V |
Patients with TB/HIV (63), adults, Rwanda | One-compartment, transit compartment absorption |
| Abdelwahab, 2020 [79] | NONMEM |
Body size, CL Body size, V |
Patients with TB/HIV (18), adults, pregnant women, South Africa | Two-compartment, transit compartment absorption |
| Levofloxacin | ||||
| Peloquin, 2008 [198] |
PASTRX, NPEM2, USC*PACK |
– | Patients with TB (10), Brazil | One-compartment |
| van den Elsen, 2018 [89] | MWPharm | – | Patients with TB (30), Belarus | One-compartment with lag time |
| Denti, 2018 [199] | NONMEM |
Body weight, CL Body weight, V |
Patients with MDR-TB (children, 109), South Africa | Two-compartment, disposition kinetics, first-order elimination and absorption |
| Al-Shaer, 2019 [200] | Monolix |
Sex, V Weight, V CrCL, CL |
Patients with TB (108), Brazil, Georgia, Bangladesh, USA | One-compartment, first-order absorption and elimination |
| Moxifloxacin | ||||
| Peloquin, 2008 [198] |
PASTRX, NPEM2, USC*PACK |
– | Patients with TB (9), Brazil | One-compartment |
| Pranger, 2011 [201] | MWPharm | – | Patients with TB (21), the Netherlands | One-compartment with first-order absorption and without lag time |
| Zvada, 2014 [202] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Patients with TB (241), Zimbabwe, South Africa | Two-compartment, with first-order elimination and transit absorption compartments |
| Chang, 2017 [203] | NONMEM | Body weight, CL | Patients with MDR-TB (14), South-Korea | One-compartment, first-order absorption |
| van den Elsen, 2019 [18] | MWPharm | – | Patients with TB (77), the Netherlands | One-compartment with lag time |
| Al-Shaer, 2019 [200] | Monolix | – | Patients with TB (70), Brazil, Georgia, Bangladesh, USA | One-compartment, first-order absorption and elimination |
| Bedaquiline | ||||
| McLeay, 2014 [99] | NONMEM |
Study, F Black race, subject status, and DS-TB, CL/F Sex, Vc/F |
Healthy adults and patients with TB (480) | Four-compartment disposition, absorption described by a dual zero-order input function |
| Svensson, 2016 [98] | NONMEM |
Body weight, CL Albumin, CL Albumin, fraction of bedaquiline metabolized to M2 |
Patients with TB (335) | Three-compartment bedaquiline and one-compartment for metabolite M2 |
| Linezolid | ||||
| Alffenaar, 2010 [204] | MWPharm | – | Patients with MDR-TB (14), the Netherlands | One-compartment with first-order absorption pharmacokinetics without lag time |
| Kamp, 2017 [115] | MWPharm | – | Patients with MDR-TB (56), the Netherlands | One-compartment |
| Garcia-Prats, 2019 [205] | NONMEM |
Body weight, CL Body weight, V |
Patients with TB (children, 48), South Africa | One-compartment |
| Alghamdi, 2020 [206] | ||||
| Clofazimine | ||||
| Nix, 2004 [119] | NONMEM | – | Healthy adults (16), USA | One-compartment |
| Abdelwahab, 2020 [120] | NONMEM |
Body weight, CL Fat-free mass, V |
Patients with TB (139), South Africa | Three-compartment, first-order elimination and absorption in transit compartments |
| Faraj, 2020 [207] | NONMEM | – | Patients with TB (15), South Africa | Two-compartment disposition, first-order absorption and elimination |
| Cycloserine/terizidone | ||||
| Chang, 2017 [203] | NONMEM | – | Patients with MDR-TB (14), South-Korea | One-compartment, first-order absorption |
| Mulubwa, 2019 [208] | Monolix | Albumin, V | Patients with TB (39), South Africa | One-compartment, modified transit compartment for terizodone absorption |
| Alghamdi, 2019 [124] | Monolix |
Healthy/TB, CL CrCL, CL Body weight, V |
Patients with TB (235), healthy adults (12), Georgia, Bangladesh, USA | One-compartment, with a first-order absorption and lag phase |
| van der Galiën, 2020 [125] | MWPharm | – | Patients with TB (17), Belarus | One-compartment, first-order absorption without lag time |
| Chirehwa, 2020 [209] | NONMEM |
Fat-free mass, CL Fat-free mass, V |
Patients with TB (132), South Africa | One-compartment disposition, with non-renal and renal clearance |
| Pretomanid | ||||
| Lyons, 2018 [210] |
GNU MCSim modeling and simulation suite |
Body weight, CL Body weight, V |
Patients with TB, adults (102), South Africa | One-compartment, first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the pre-dose fed state |
| Salinger, 2019 [211] | NONMEM |
Body weight, CL Body weight, V |
Healthy adults and patients with TB (1054) | One-compartment |
| Amikacin | ||||
| Dijkstra, 2015 [156] | MWPharm | Sex, V | Patients with TB (20), the Netherlands | One compartment |
| Ethionamide/prothionamide | ||||
| Zhu, 2002 [162] |
PASTRX, NPEM2, USC*PACK |
– | Patients with TB (55), USA | One-compartment |
| Nyberg, 2020 [212] | NONMEM |
Nasogastric administration HIV, F Rifampicin, CL Body weight, CL Body weight, V |
Patients with TB (children, 110), South Africa | One-compartment disposition model with first-order elimination and a transit compartment absorption |
| Al-Shaer, 2020 [213] | Pmetrics | – | Patients with TB (94), Bangladesh, USA | One-compartment, first-order elimination and absorption lag time |
| Para-aminosalicylic acid | ||||
| de Kock, 2014 [167] | NONMEM | Efavirenz, CL | Patients with TB (73), South Africa | One-compartment disposition, absorption described by a 3-transit compartment |
| Chang, 2017 [203] | NONMEM | – | Patients with MDR-TB (14), South-Korea | One-compartment with first-order absorption |
| Abulfathi 2020 [214] |
NONMEM Modification of de Kock, 2014 [167] |
Body weight, CL Body weight, V |
Patients with TB (73), South Africa | One-compartment disposition with 3-transit absorption compartments |
AIDS acquired immunodeficiency syndrome, CL clearance, CL/F apparent clearance, CrCL creatinine clearance, CYP cytochrome P450, DS drug-susceptible, F bioavailability, FDC fixed dose combination, HIV human immunodeficiency virus, IT2B iterative two-stage Bayesian procedure, Ke elimination rate constant, MDR multi-drug resistant, MTT mean transit time, NAT2 N-acetyl transferase 2, SDF single dose formulation, TB tuberculosis, V volume of distribution, Vc/F apparent central volume of distribution