Kinetic Studies on Rifampicin

Acocella, G; Pagani, V.; Marchetti, M.; Baroni, Gaia; Nicolis, F. B.

doi:10.1159/000220750

Cited by 85 publications

(19 citation statements)

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“…The model suggests that, on average, clearance of rifampin almost doubles from the first day of treatment to steady state, and the induction process takes around 2 weeks to reach 90% of the fully induced state. The duration of the process differs from that reported in other studies, possibly because of the richness of data and the dosing strategies used (daily versus intermittent dosing) (11,28). Though the induction half-life estimated by our model is shorter than that reported by Smythe et al, the extent of the autoinduction effect on clearance is roughly the same.…”

Section: Discussioncontrasting

confidence: 73%

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Chirehwa

Rustomjee

Mthiyane

et al. 2016

Antimicrob Agents Chemother

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Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TBcoinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4. Rifampin is a key drug in the treatment of tuberculosis (TB), and the World Health Organization (WHO) currently recommends weight-adjusted doses of 8 to 12 mg/kg daily. Despite its being used in the treatment of TB for nearly 50 years, there is evidence that current rifampin exposures may be suboptimal. Rifampin's efficacy is exposure dependent (1-3); therefore, the efficacy and toxicity of higher doses are under investigation. Recent reports show that larger doses of rifampin are well tolerated by humans (4) and may improve treatment outcomes, as well as reduce the treatment duration from the current 6 months (5, 6).Rifampin is mainly hepatically cleared, and it undergoes extensive first-pass metabolism (7), whose saturation with higher doses has been reported since early pharmacokinetic (PK) studies (8). Thus, when the rifampin dose is increased above a certain level, a more-than-proportional increase in the plasma rifampin concentration results. Rifampin also induces its own metabolism via the pregnane X receptor (9), a phenomenon known as clearance autoinduction, resulting in less exposure at steady state than after a single dose.Previous studies have proposed rifampin PK models (10), but those trying to characterize clearance autoinduction have done so mostly by relying on only two PK sampling occasions (11), which limited their ability to characterize the process. Nonlinearity in a dose-exposure relationship suggesting saturation of rifampin clearance has been reported (8). However, a population PK model has not jointly described the autoinduction and hepatic extraction (E H ) of rifampin. In this study, we analyzed rich data from an intensive sampling scheme to develop a rifampin PK model for TB patients that accounts for both clearance autoinduction and saturation of E H . This model was then employed to explore changes in rifampin exposure when doses are incr...

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Section: Discussioncontrasting

confidence: 73%

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Chirehwa

Rustomjee

Mthiyane

et al. 2016

Antimicrob Agents Chemother

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“…The plasma rifampicin pharmacokinetic profiles seen in this study are similar to those described previously [13,18,19], with a similar apparent volume of distribution and elimination half life. However, this is the first study, to our knowledge, that attempts to determine the accumulation of rifampicin in PBMCs in vivo in tuberculosis patients.…”

Section: Discussionsupporting

confidence: 87%

A rapid and sensitive HPLC–MS method for the detection of plasma and cellular rifampicin

Hartkoorn

Khoo

Back

et al. 2007

Journal of Chromatography B

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“…Autoinduction of RIM metabolism in humans was studied by Acocella et al (48) and more recently by Loos et al (49). In the study by Acocella et al, three dose levels, each in six healthy subjects, were investigated: 900 mg and 600 mg once daily and 300 mg administered at 12-hr intervals.…”

Section: Inducton Properties Of Rifampicin and Rifabutin In Animalsmentioning

confidence: 99%

Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies.

Benedetti¹,

Dostert²

1994

Environ Health Perspect

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Animal studies have demonstrated that the mouse and rabbit are far more responsive to the inductive properties of rifamycin derivatives than the rat and guinea pig. The rat hepatic cytochrome P450 system seems to be resistant to the action of rifampicin unless very high doses are used. Mouse hepatic microsomal mixed-function oxidase activity is markedly increased by repeated dosing with rifampicin, whereas administration of rifabutin may be ineffective. In humans, both rifampicin and rifabutin are extensively metabolized and induce their own metabolism. The induced metabolic pathways remain essentially unknown. Under autoinduction conditions, the elimination half-life of rifampicin decreases, whereas that of rifabutin is not altered. Although the effects of repeated administration of rifampicin and rifabutin on the various forms of cytochrome P450 in humans have not been extensively examined, there is convincing evidence that the P4503A subfamily is induced by either drug, whereas the P4501 A subfamily and P4502D6 do not appear to be affected by rifampicin. Limited reliable information is available concerning the induction of human glucuronyltransferase activities by rifampicin and rifabutin which, however, do not seem to influence zidovudine glucuronide formation in healthy subjects.

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Kinetic Studies on Rifampicin

Cited by 85 publications

References 0 publications

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

A rapid and sensitive HPLC–MS method for the detection of plasma and cellular rifampicin

Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies.

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