Plasma Concentrations Of Rifampin Research Articles

Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients.

Rifampin (RF) is metabolized in the liver into an active metabolite 25-desacetylrifampin and excreted almost equally via biliary and renal routes. Various influx and efflux transporters influence RF disposition during hepatic uptake and biliary excretion. Evidence has also shown that Vitamin D deficiency (VDD) and Vitamin D receptor (VDR) polymorphisms are associated with tuberculosis (TB). Hence, genetic polymorphisms of metabolizing enzymes, drug transporters and/or their transcriptional regulators and VDR and its pathway regulators may affect the pharmacokinetics of RF. In this narrative review, we aim to identify literature that has explored the influence of single nucleotide polymorphisms (SNPs) of genes encoding drug transporters and their transcriptional regulators (SLCO1B1, ABCB1, PXR and CAR), metabolizing enzymes (CES1, CES2 and AADAC) and VDR and its pathway regulators (VDR, CYP27B1 and CYP24A1) on plasma RF concentrations in TB patients on antitubercular therapy. Available reports to date have shown that there is a lack of any association of ABCB1, PXR, CAR, CES1 and AADAC genetic variants with plasma concentrations of RF. Further evidence is required from a more comprehensive exploration of the association of SLCO1B1, CES2 and Vitamin D pathway gene variants with RF pharmacokinetics in distinct ethnic groups and a larger population to reach conclusive information.

English

Rifampin is one of first-line drugs for the treatment of tuberculosis. In Indonesia nearly all tuberculosis patients show lower rifampin plasma concentrations possibly due to genetics. Rifampin is a substrate of the organic anion-transporting polypeptide 1B1 (OATP 1B1) encoded by the solute carrier organic anion transporter family member 1B1 (SLCO1B1). This study aimed to identify haplotype polymorphisms of tuberculosis drug transporters with an impact on clinical outcome in tuberculosis patients. Thirty-six patients from Abdul Wahab Sjahranie General Hospital, Samarinda, East Kalimantan were involved in the study. Buffy coat from patient blood samples were tested for SLCO1B1 and SLCO1B3 polymorphisms by RFLP and ARMS PCR, whereas the clinical outcome was examined based on the sputum conversion. The frequency of patients with SLCO1B1*15 haplotype was 63.9%. The SLCO1B1*15 haplotype was associated with susceptibility to failure of clinical outcome (p=0.005; RR=4.52; 95% CI: 1.22-16.64). The OATP1B1*15 haplotype revealed that the failure of clinical outcome was markedly increased compared to the three other haplotypes. These results suggest that the SLCO1B1*15 haplotype is an important predisposing factor for lower clinical outcome. Our data indicate that individualized treatment should be considered for Indonesian tuberculosis patients based on genetics characteristics of patients.

Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis.

Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0-24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m(2)) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (+14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC0-24) of 5.6 μg/ml and 28.6 μg · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher Cmax and AUC0-24 values of 6.4 μg/ml and 31.6 μg · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.).

Dramatic reduction of clindamycin plasma concentration in hidradenitis suppurativa patients treated with the rifampin-clindamycin combination

The oral clindamycin-rifampin combination is a treatment option of hidradenitis suppurativa (HS) [1–3]. The following report suggests that a significant pharmacokinetic interaction exists between the two drugs that may alter the efficacy of the treatment.In July 2007, the clindamycin and rifampin plasma concentrations were measured in a 26-year-old HS patient who did not respond to a standard dosing regimen of clindamycin (20-40 mg/kg/day, tid) and rifampin (20 mg/kg/day, bid). The trough level [...]

Pharmacokinetics of Rifampin in Peruvian Tuberculosis Patients with and without Comorbid Diabetes or HIV

For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (C(max)) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin C(max) was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P < 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different C(max) results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P < 0.001) and the time to maximum concentration of drug in serum (T(max)) at 2 h (P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.

The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.

Inhibitory effects of ketoconazole and rifampin on OAT1 and OATP1B1 transport activities: considerations on drug–drug interactions

Ketoconazole and rifampin are the most widely used compounds examined in recent drug-drug interaction (DDI) studies, and they have multiple roles in modulating drug metabolizing enzymes and transporters. To determine the underlying mechanisms of DDI, this study was performed to investigate the inhibitory effects of ketoconazole and rifampin on the functions of OAT1 and OATP1B1, and to evaluate the potential of ketoconazole and rifampin for DDI with substrate drugs for these transporters in a clinical setting. Ketoconazole inhibited OATP1B1-mediated transport activity, while rifampin inhibited OAT1 and OATP1B1. Inhibition by rifampin and ketoconazole of the uptake of olmesartan, a substrate for OAT1 and OATP1B1, was evaluated in oocytes overexpressing these transporters. The K(i) values for rifampin on OAT1 and OATP1B1-mediated olmesartan uptake were 62.2 and 4.42 µM, respectively, and the K(i) value for ketoconazole on OATP1B1-mediated olmesartan uptake was 66.1 µM. As measured plasma concentrations of rifampin and ketoconazole were 7.29 and 6.4-13.3 µM, respectively, the likelihood of an OATP1B1-mediated drug-drug interaction between rifampin and olmesartan is thought to be possible, whereas OAT1 or OATP1B1-mediated DDI between rifampin or ketoconazole and olmesartan appears unlikely in the clinical setting.

Rifampin levels, interferon-gamma release and outcome in complicated pulmonary tuberculosis

Factors that relate to medium-term outcome in patients with pulmonary tuberculosis (PTB) who have completed the 2-month intensive phase of treatment are incompletely understood. The relationship between in vitro production of interferon-gamma (IFN-gamma), interleukins (ILs)-5 and -10 and drug levels determined after 2 months of drug therapy, to outcome at 24 months was studied prospectively. Cytokine concentrations were determined from culture supernatants after stimulation of whole blood with purified protein derivative (PPD) of Mycobacterium tuberculosis. Plasma concentrations of rifampin, isoniazid, pyrazinamide and ethambutol were determined by high-performance liquid chromatography. The treatment failure and relapse free survival probability was 0.54 (95% CI: 0.40-0.67) at 24 months. In multivariate analysis of parameters at 2 months the strongest positive associations with disease free survival were IFN-gamma response to PPD (p=0.002) and serum creatinine (p=0.001). Drug concentrations were not associated with outcome although rifampin exposure correlated with IFN-gamma response to PPD (p=0.0132). These data suggest that the ability to mount a recall immune response to M. tuberculosis may influence treatment outcome. The data support the idea to identify persons at risk of a poor treatment outcome by monitoring of the in vitro response to tuberculosis antigens.

Rifampin Induces the in Vitro Oxidative Metabolism, but Not the in Vivo Clearance of Diclofenac in Rhesus Monkeys

Effects of rifampin on in vitro oxidative metabolism and in vivo pharmacokinetics of diclofenac (DF), a prototypic CYP2C9 marker substrate, were investigated in rhesus monkeys. In monkey hepatocytes, rifampin markedly induced DF 4'-hydroxylase activity, with values for EC(50) of 0.2 to 0.4 microM and E(max) of 2- to 5-fold over control. However, pretreatment with rifampin did not alter the pharmacokinetics of DF obtained after either i.v. or intrahepatic portal vein (i.pv.) administration of DF to monkeys. At the dose studied, plasma concentrations of rifampin reached 10 microM, far exceeding the in vitro EC(50) values. Under similar treatment conditions, rifampin was previously shown to induce midazolam (MDZ) 1'-hydroxylation in rhesus monkey hepatocytes (EC(50) and E(max) values approximately 0.2 microM and approximately 2- to 3-fold, respectively), and markedly affected the in vivo pharmacokinetics of MDZ (>10-fold decreases in the i.pv. MDZ systemic exposure and its hepatic availability, F(h)) in this animal species. In monkey liver microsomes, DF underwent, predominantly, glucuronidation, and, modestly, oxidation; the intrinsic clearance (CL(int) = V(max)/K(m)) value for the glucuronidation pathway accounted for >95% (versus about 75% in human liver microsomes) of the total (glucuronidation + hydroxylation) intrinsic clearance value. In monkey hepatocytes, the hydroxylation also was a minor component (< or =10%) relative to the glucuronidation, supporting the liver microsomal finding. Collectively, our results suggest that the oxidative metabolism is not the major in vivo clearance mechanism of DF in either untreated or rifampin-treated monkeys and, conceivably, also in humans, raising a question about the utility of DF as an in vivo CYP2C9 probe.

In Vitro and in Vivo CYP3A64 Induction and Inhibition Studies in Rhesus Monkeys: A Preclinical Approach for CYP3A-Mediated Drug Interaction Studies

In this study, induction and inhibition of rhesus monkey CYP3A64 versus human CYP3A4 were characterized in vitro, and the corresponding pharmacokinetic consequences were evaluated in rhesus monkeys. In monkey hepatocytes, rifampin markedly induced CYP3A64 mRNA (EC50 = 0.5 microM; Emax = 6-fold) and midazolam (MDZ) 1'-hydroxylase activity (EC50 = 0.2 microM; Emax = 2-fold). Compound A (N-[2(R)-hydroxy-1(S)-indanyl-5-[2(S)-(1,1-dimethylethylaminocarbonyl)-4-[(furo[2,3-b]pyridin-5-yl)-methyl]piperazin-1-yl]-4(S)-hydroxy-2(R)-phenylmethylpentanamide), a known potent and mechanism-based inhibitor of CYP3A4, strongly inhibited the formation of 1'-hydroxy MDZ by recombinant CYP3A64 in a concentration- and time-dependent manner (KI = 0.25 microM; k(inact) = 0.4 min(-1)). Similar corresponding results also were obtained with human CYP3A4 in the presence of rifampin or compound A. In rhesus monkeys, MDZ exhibited a relatively high metabolic clearance (primarily via 1'-hydroxylation followed by glucuronidation) and a low hepatic availability (Fh = 16%). Consistent with the induction of hepatic metabolism of a high-clearance compound, pretreatment with rifampin (18 mg/kg p.o. for 5 days) did not significantly affect the i.v. kinetics of MDZ, but caused a pronounced reduction (approximately 10-fold) in the systemic exposure to MDZ and, consequently, its Fh following intrahepatic portal vein administration (i.pv.) of MDZ. A comparable extent of the pharmacokinetic interaction also was obtained after a 1.8 mg/kg rifampin dose. Also consistent with the in vitro CYP3A64 inhibition finding, compound A (6 mg/kg i.v.) markedly increased (10-fold) the i.pv. administered MDZ exposure. At the doses studied, plasma concentrations of rifampin or compound A reached or exceeded their respective in vitro EC50 or KI values. These findings suggest the potential applicability of the in vitro-in vivo relationship approach in rhesus monkeys for studying CYP3A-mediated interactions in humans.

Evaluation of High- versus Standard-Dose Rifampin in Indonesian Patients with Pulmonary Tuberculosis

We previously found peak plasma concentrations of rifampin below 4 mg/liter in 70% of Indonesian tuberculosis (TB) patients treated with 10 mg rifampin/kg of body weight daily (6), much below the reference concentration of ≥8 mg/liter (5). In addition, both murine models (1) and studies with TB patients (3) suggest that the typical 10-mg/kg dose of rifampin may be too low and that a higher dose may reduce treatment duration (4). Indeed, a regimen incorporating a higher dose of 1,200 mg rifampin daily yielded much faster conversion of sputum culture (2). Based on these findings, we decided to investigate the effect of increasing the dose of rifampin in terms of pharmacokinetics and tolerability. In an open-label phase II randomized clinical trial in an urban clinic in Indonesia, consecutive patients with microbiologically proven pulmonary TB were randomized to a standard (450 mg; 10 mg/kg) or high (600 mg) dose of rifampin. High and standard doses of rifampin were administered every day in the intensive phase and three times weekly in the continuation phase of treatment. All other TB drugs were dosed according to the protocols of the Indonesian National TB Program. All patients provided written informed consent, and the study was approved by the local institutional review board. After 4 and 8 weeks of treatment, blood samples were collected at the time of peak plasma concentration of rifampin, 2 hours (5) after the witnessed intake of TB drugs on an empty stomach. Plasma was separated immediately and stored at −80°C until measurement of rifampin concentrations with a validated high-performance liquid chromatographic assay. Patients were questioned actively for possible adverse events, and liver transaminases were monitored. The simultaneous effects of the dose of rifampin and the week of treatment on the rifampin peak plasma concentrations were evaluated with a two-way mixed analysis of variance. Fifty patients were included, and 46 completed the study (54% male; median age, 25 years; range, 18 to 50 years). Patients from both groups had similar body weights, and the median dose of rifampin corresponded to 13.3 mg/kg in the 600-mg-dose group and 10.3 mg/kg in the 450-mg-dose group. The mean peak plasma concentration of rifampin was higher in the 600-mg-dose group (11.1 versus 8.0 mg/liter; F = 8.77; P = 0.005). Mean plasma concentrations were similar in weeks 4 and 8. In week 4, the percentages of patients with rifampin peak plasma concentrations of ≥8 mg/liter were 48% (for the 450-mg dose) and 78% (for the 600-mg dose) (χ2; P = 0.03) (Fig. ​(Fig.1).1). One patient receiving 600 mg developed a reversible elevation of the liver transaminase level to >5 times normal, while four patients (two in each study arm) showed mildly elevated transaminase levels. No differences were noted in terms of tolerability. FIG. 1. Two-hour plasma rifampin concentrations after 4 weeks of TB treatment in Indonesian patients randomized to standard-dose (450 mg) or high-dose (600 mg) rifampin daily. Rifampin doses were combined with standard-dose isoniazid, pyrazinamide, and ethambutol. ... In conclusion, this trial in Indonesia shows that a higher dose of rifampin significantly increases the proportion of patients with rifampin peak plasma concentrations above the reference value of 8 mg/liter. Blinded studies with more-extensive pharmacokinetic assessments will provide more insight into the merits of high-dose rifampin and may pave the road for studies evaluating high-dose rifampin in shorter treatment regimens.

Effect of rifampin (RIF) on the pharmacokinetics (PK) of atrasentan (ABT-627, ATN)

4728 Background: ATN, an oral endothelin antagonist with high selectivity for ETA receptor, is currently in phase 3 clinical development for the treatment of hormone-refractory prostate cancer. In humans, oral ATN is extensively metabolized, equally distributed between oxidation and glucuronidation. In vitro, CYP3A was the predominant isozyme involved in oxidative metabolism. The antibiotic RIF is a potent inducer of metabolic enzymes, including CYP3A, and is recommended by FDA as a probe of choice to determine the maximal inducing effect on a CYP3A-metabolized drug. RIF is also known to inhibit the liver basolateral uptake transporters OATP-C and OATP8. Methods: To assess the effect of RIF on ATN PK, a phase 1 open label study was conducted in 12 healthy male subjects (mean±SD 36±11 yrs, 78±10 kg). Subjects received ATN 10 mg PO on Days 1 and 12. RIF 600 mg PO QD was given from Day 4 through 14. Blood samples for ATN assay were collected predose and over 72 h after each ATN dose. Plasma concentrations of ATN were determined using a validated LC/MS/MS method. Results: ATN PK are summarized (mean±SD; N=12) in the following table. ATN with RIF was generally well tolerated; all AEs were mild. Conclusions: Effects on ATN PK by RIF co-administration were consistent with a biphasic interaction hypothesis. In the early phase (first several h), RIF competitively inhibited ATN uptake by the liver. In the later phase, when RIF plasma concentrations were low, the interaction was dominated by CYP3A induction. RIF co-administration is expected to have similar effects on steady-state ATN PK, and is therefore expected to be well-tolerated and have little if any effect on atrasentan efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories

Effect of rifampin (RIF) on the pharmacokinetics (PK) of atrasentan (ABT-627, ATN)

4728 Background: ATN, an oral endothelin antagonist with high selectivity for ETA receptor, is currently in phase 3 clinical development for the treatment of hormone-refractory prostate cancer. In humans, oral ATN is extensively metabolized, equally distributed between oxidation and glucuronidation. In vitro, CYP3A was the predominant isozyme involved in oxidative metabolism. The antibiotic RIF is a potent inducer of metabolic enzymes, including CYP3A, and is recommended by FDA as a probe of choice to determine the maximal inducing effect on a CYP3A-metabolized drug. RIF is also known to inhibit the liver basolateral uptake transporters OATP-C and OATP8. Methods: To assess the effect of RIF on ATN PK, a phase 1 open label study was conducted in 12 healthy male subjects (mean±SD 36±11 yrs, 78±10 kg). Subjects received ATN 10 mg PO on Days 1 and 12. RIF 600 mg PO QD was given from Day 4 through 14. Blood samples for ATN assay were collected predose and over 72 h after each ATN dose. Plasma concentrations of ATN were determined using a validated LC/MS/MS method. Results: ATN PK are summarized (mean±SD; N=12) in the following table. ATN with RIF was generally well tolerated; all AEs were mild. Conclusions: Effects on ATN PK by RIF co-administration were consistent with a biphasic interaction hypothesis. In the early phase (first several h), RIF competitively inhibited ATN uptake by the liver. In the later phase, when RIF plasma concentrations were low, the interaction was dominated by CYP3A induction. RIF co-administration is expected to have similar effects on steady-state ATN PK, and is therefore expected to be well-tolerated and have little if any effect on atrasentan efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories