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/m²) 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 (C_max) and area under the concentration-time curve from 0 to 24 h (AUC_0–24) of 5.6 μg/ml and 28.6 μg · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher C_max and AUC_0–24 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.)     

Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC_0–∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC_0–∞ of 41.2 μg · h/ml decreased on average by 14.3% (90% confidence interval [CI], −90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of ≥125 only when the MIC was <0.125 μg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385.)     

Effects of Dosage,Comorbidities, and Food on Isoniazid Pharmacokinetics in Peruvian Tuberculosis Patients

Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic (PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This study aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e., biweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric methods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (P < 0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration (C_max) and area under the concentration-time curve from 0 to 6 h (AUC_0–6) were 2.77 mg/liter and 9.71 mg·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration. There were no differences in the C_max with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with lower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during the continuation phase did not reach the C_max reference value. However, low levels of INH were not associated with poorer clinical outcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate any effect on PK. We were unable to demonstrate a clear relationship between the C_max and treatment outcome in this data set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential patient factors under program conditions.     

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Concomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals'' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed. (These studies have been registered at ClinicalTrials.gov under registration numbers {"type":"clinical-trial","attrs":{"text":"NCT00828529","term_id":"NCT00828529"}}NCT00828529 [study C110] and {"type":"clinical-trial","attrs":{"text":"NCT00910806","term_id":"NCT00910806"}}NCT00910806 [study C117].)     

Pharmacokinetics of Antituberculosis Drugs in Pulmonary Tuberculosis Patients with Type 2 Diabetes

Altered pharmacokinetics of antituberculosis drugs may contribute to an increased risk of tuberculosis treatment failure for diabetic patients. We previously found that rifampin exposure was 2-fold lower in diabetic than in nondiabetic tuberculosis patients during the continuation phase of treatment. We now examined the influence of diabetes on the pharmacokinetics of antituberculosis drugs in the intensive phase of tuberculosis treatment, and we evaluated the effect of glycemic control. For this purpose, 18 diabetic and 18 gender- and body weight-matched nondiabetic tuberculosis patients were included in an Indonesian setting. Intensive pharmacokinetic sampling was performed for rifampin, pyrazinamide, and ethambutol at steady state. The bioavailability of rifampin was determined by comparing rifampin exposure after oral versus intravenous administration. Pharmacokinetic assessments were repeated for 10 diabetic tuberculosis patients after glycemic control. No differences in the areas under the concentration-time curves of the drugs in plasma from 0 to 24 h postdose (AUC_0-24), the maximum concentrations of the drugs in plasma (C_max), the times to C_max (T_max), and the half-lives of rifampin, pyrazinamide, and ethambutol were found between diabetic and nondiabetic tuberculosis patients in the intensive phase of tuberculosis treatment. For rifampin, oral bioavailability and metabolism were similar in diabetic and nondiabetic patients. The pharmacokinetic parameters of antituberculosis drugs were not correlated with blood glucose levels or glucose control. We conclude that diabetes does not alter the pharmacokinetics of antituberculosis drugs during the intensive phase of tuberculosis treatment. The reduced exposure to rifampin of diabetic patients in the continuation phase may be due to increased body weight and possible differences in hepatic induction. Further research is needed to determine the cause of increased tuberculosis treatment failure among diabetic patients.Diabetes mellitus (DM) is a well-known risk factor for tuberculosis (TB) (1, 3, 7), with prevalence rates among TB patients ranging from 10 to 30% (1, 24, 25). There is a rapid increase in the global prevalence of DM, especially in developing countries, where TB is highly endemic. It is estimated that by the year 2030, 80% of DM patients will live in the high-burden countries for TB (28). As a result, the number of TB patients with DM will increase further (19).Diabetes exerts a negative effect on TB treatment, especially among patients with poor glycemic control, with more treatment failure and more relapse than among TB patients in general (2, 3, 7, 24). One of the possible underlying mechanisms could be altered pharmacokinetics of anti-TB drugs. Lower concentrations of anti-TB drugs in plasma have been associated with clinical failure and acquired drug resistance (11, 23). Our previous study showed that the mean exposure to rifampin (expressed as the area under the concentration-time curve of the drug in plasma from 0 to 6 h postdose [AUC_0-6]) and the mean peak concentration of the drug in plasma (C_max) were 2-fold lower in Indonesian TB patients with DM than in those without DM (14). In multivariate analyses, a higher body weight (P < 0.001), the presence of DM (P = 0.06), and higher blood glucose levels (P = 0.016) contributed to lower plasma rifampin concentrations. These results suggested that heavier diabetic TB patients may need to be treated with a higher dose of rifampin and that glycemic control may increase drug concentrations.In our previous study, TB patients with and without DM were not matched for weight (6, 15); only rifampin was measured; and limited sampling points were used to assess the pharmacokinetics of this drug. We have therefore performed an in-depth follow-up study in which TB patients with and without DM were matched for weight in order to enable disentangling of the effects of DM and weight on plasma drug concentrations. Furthermore, rifampin, pyrazinamide, and ethambutol were studied, and intensive pharmacokinetic sampling was performed. The first objective of the study was to compare the pharmacokinetics of rifampin, pyrazinamide, and ethambutol between weight-matched diabetic and nondiabetic TB patients. The second objective was to elaborate the possible mechanism of the alteration of pharmacokinetics of rifampin, and the third was to evaluate the effect of glycemic control on the pharmacokinetics of anti-TB drugs in diabetic TB patients.     

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC_0–24) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC_0–24/MIC ratios of ≥53 and ≥100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of ≥53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of ≥100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.     

N-Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para-Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

The aim of this study was to examine the relationships between N-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients'' NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3, NAT1*14, and NAT2*5 alleles corresponded to 25, 37, −17, −48, and −27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele.     

A Systematic Review and Meta-analysis of Isoniazid Pharmacokinetics in Healthy Volunteers and Patients with Tuberculosis

PurposeThis systematic review and meta-analysis assesses the pharmacokinetic (PK) summary estimates of isoniazid (INH) between healthy volunteers and patients with tuberculosis (TB), evaluates whether the current INH dose regimen is appropriate in patients with TB, and evaluates the impact of N-acetyl-transferase-2 (NAT2) status on the PK properties of INH.MethodsA systematic approach was conducted to find studies with relevant INH PK data published in the English language up to February 2018. The PK properties of INH were extracted with their respective INH dosages and were dose normalized to allow a fair comparison between healthy volunteers and patients with TB. Meta-analysis was then performed for the C_max and AUC estimates for all INH dosages.FindingsNinety studies were included in this systematic review. TB status significantly affected the INH C_max and AUC estimates. In healthy volunteers, the dose-normalized INH C_max and AUC were statistically higher than those of patients with TB. No significant differences were found in dose-normalized C_max and AUC between adults with TB and adults with TB/HIV; however, the AUC in pediatric patients was significantly different between patients with TB and patients with TB/HIV. In addition, no significance was observed comparing the dose-normalized C_max and AUC of pediatric patients with TB and TB/HIV with their respective adult counterparts. Dose-normalized INH C_max and AUC in patients with fast and intermediate NAT2 were significantly lower than in patients with slow NAT2.ImplicationsThe current recommended dosages of INH were found to produce less drug exposure in patients with TB when compared with healthy volunteers. NAT2 polymorphism greatly impacts the PK properties of INH; hence, testing for acetylator status is highly recommended, and therapeutic drug monitoring would help reduce INH toxicity.     

Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C_maxs, and C_mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C_min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.Tipranavir (TPV; Aptivus) is an approved protease inhibitor (PI) with potent activity against multiple-PI-resistant human immunodeficiency virus type 1 (HIV-1). The RESIST clinical studies showed better virological and immunological responses over 48 weeks with patients with extensive treatment experience for TPV-ritonavir (RTV) (TPV/r) with an optimized background regimen then with optimized boosted PI therapy (6). TPV is metabolized by cytochrome P450 3A4 (CYP3A4), and to achieve effective plasma TPV concentrations and a twice-daily (BID) dosing regimen with treatment-experienced patients, coadministration of TPV 500 mg with 200 mg of RTV (TPV/r) is essential (10). The TPV/r combination has both inducing and inhibiting effects on several CYP enzymes and has been shown to be a net inducer of CYP3A4 (M. Vourvahis, J. Dumond, K. Patterson, N. Rezk, N. White, S. Jennings, H. Tien, J. Sabo, T. MacGregor, and A. Kashuba, Effects of tipranavir/ritonavir [TPV/r] on the activity of hepatic and intestinal cytochrome P450 3A4/5 and P-glycoprotein [P-gp]: implications for drug interactions, presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, 2007). As a result, drug interactions are to be expected when combining TPV/r with other medications (17). The combination of TPV/r with efavirenz (EFV) is an option in the treatment of HIV-infected individuals and should be assessed for possible drug interactions. Previously it has been shown that TPV/r does not affect EFV concentrations when administered together to healthy volunteers (13) and to HIV-1-infected patients (F. D. Goebel, J. P. Sabo, T. R. MacGregor, D. L. Mayers, and S. McCallister, Pharmacokinetic drug interaction screen of three doses of tipranavir/ritonavir [TPV/r] in HIV-infected patients on stable highly active antiretroviral therapy [HAART], presented at HIV DART Conference, Naples, FL, 2002). The objective of the current study was to determine the effects of steady-state EFV 600 mg once a day (QD) on the steady-state pharmacokinetics of TPV 500 mg and RTV 200 mg, both administered BID. The primary pharmacokinetic (PK) endpoints were area under the concentration-time curve (AUC), maximum concentration of drug in plasma (C_max), and minimum concentration of drug in plasma (C_min) for TPV and RTV. The secondary endpoints included other PK parameters as well as AEs (adverse events) and clinical laboratory test results.     

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.)     

Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients

PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log₁₀ CFU/day/ml (± standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (±0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (±0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.Over four decades ago, the introduction of rifampin catalyzed a series of clinical trials leading to current recommendations for tuberculosis (TB) treatment, with the combination of isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA), supported by ethambutol (EMB) or streptomycin (SM) (17, 27). However, this regimen must be taken consistently for 6 months, preferably under supervision, to ensure sterilization of tuberculosis lesions and to prevent development of drug resistance. This relatively long treatment duration, coupled with increasing financial and administrative difficulties experienced by health care systems and the burgeoning HIV/AIDS epidemic, threatens the success of tuberculosis control programs worldwide, particularly in high-incidence areas such as sub-Saharan Africa and parts of Asia. Treatment default is all too frequent (14), and the situation is further exacerbated by the increasing proportion of new cases of tuberculosis resistant to one or more first-line agents (7, 28). New drugs are urgently needed to meet these challenges. They are needed to assist in the management of drug resistance, but also, at least as importantly, to assist in shortening treatment regimens to make tuberculosis treatment easier to supervise and reduce the therapeutic burden that tuberculosis management places on both patients and health services. In addition, current regimens cause difficulties for tuberculosis patients coinfected with HIV due to the deleterious interaction of existing first-line antituberculosis drugs and antiretroviral agents.PA-824 is a small nitroimidazo-oxazine molecule that has shown potential both in vitro and in vivo of being able to assist both in shortening the treatment regimen for tuberculosis and contributing to the treatment of drug-resistant tuberculosis patients (19, 20). Studies using anaerobic culture models have also found activity against nonreplicating Mycobacterium tuberculosis (10, 16, 24, 25). In vitro studies found the MIC of PA-824 (≤0.015 to 0.25 μg/ml) to be comparable to that of INH (0.03 to 0.06 μg/ml) (16). Studies in healthy volunteers indicated that PA-824 was well tolerated and bioavailable after oral doses without significant drug-related side effects, changes in vital signs, or abnormal laboratory values (8, 9). PA-824 has been shown to cause isolated and reversible increases in serum creatinine levels, which appear to be due to inhibition of creatinine secretion and are considered clinically benign (8, 9). The dosage levels of 200 mg, 600 mg, 1,000 mg, and 1,200 mg used in this study were selected on the basis of preclinical toxicology and efficacy data and clinical pharmacokinetic properties of PA-824 observed in healthy adult volunteers and were chosen to assist identification of the lowest efficacious dosage and the highest dosage safely inducing maximal bactericidal efficacy.Early bactericidal activity (EBA) refers to an agent''s ability to kill mycobacteria originating within pulmonary cavities during the first weeks of treatment. Determination of EBA in sputum smear-positive pulmonary tuberculosis patients by quantification of viable CFU of M. tuberculosis in an overnight sputum collection allows the comparison of different drugs with one another with regard to clinical bactericidal activity and early assessment of safety in a small number of intensively studied patients. The evaluation of a dosage-related response can guide the selection of a dosage to take forward to later clinical studies (5, 6, 12, 13). Initial studies using this technique were conducted over the first two days of treatment, as it was during this period that the most significant differences between agents were seen (12). Further experience has shown that significant advantages may accrue from extending the study period; for example, the important sterilizing agent PZA showed bactericidal activity only after four days of treatment (12), as did the novel diarylquinoline currently in development, TMC207 (4, 23).It has also been suggested that activity during the period of 2 to 14 days after treatment is started might represent the sterilizing capacity of an agent (13). Recently, evidence has been presented that the time to positivity (TTP) of M. tuberculosis in automated liquid culture systems reflects the metabolic activity of inoculated viable M. tuberculosis in sputum. TTP might represent an alternative method to colony counting for estimating the activity of viable M. tuberculosis in sputum, which might be valuable for exploring the bactericidal activities of new antituberculosis agents (22).This paper reports a proof-of-concept study that evaluated the bactericidal activity of PA-824 given as monotherapy over a range of dosages during the first 14 days of treatment of treatment-naïve patients with smear-positive pulmonary tuberculosis. Safety, tolerability, and pharmacokinetics (PK) were also evaluated.     

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto,South Africa

Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks'' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC_0–24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear.     

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety,BMS-626529

BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4⁺ T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8⁺ T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the log_e-transformed concentration at the end of a dosing interval (C_tau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC₅₀) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log₁₀ copies/ml as a function of the log_e-transformed PBAIC₅₀-adjusted C_tau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers {"type":"clinical-trial","attrs":{"text":"NCT01009814","term_id":"NCT01009814"}}NCT01009814 and {"type":"clinical-trial","attrs":{"text":"NCT01384734","term_id":"NCT01384734"}}NCT01384734, respectively.)     

Pharmacokinetics of para-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy,Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Forty-one pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regimens was developed; potential covariates affecting its pharmacokinetics were examined, and Monte Carlo simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. The probability of target attainment (PTA) to maintain PAS levels above MIC during the dosing interval was estimated by simulation of once-, twice-, and thrice-daily dosing regimens not exceeding 12 g daily. Concurrent efavirenz (EFV) medication resulted in a 52% increase in PAS clearance and a corresponding >30% reduction in mean PAS area under the concentration curve in 19 of 22 HIV-M. tuberculosis-coinfected patients. Current practice recommends maintenance of PAS concentrations at ≥1 μg/ml (the MIC of M. tuberculosis), but the model predicts that at only a minimum dose of 4 g twice daily can this PTA be achieved in at least 90% of the population, whether or not EFV is concomitantly administered. Once-daily dosing of 12 g PAS will not provide PAS concentrations exceeding the MIC over the entire dosing interval if coadministered with EFV, while 4 g twice daily ensures concentrations exceeding MIC over the entire dosing interval, even in HIV-infected patients who received EFV.     

Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV

PurposeThe updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women.MethodsGhanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared.FindingsOf 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The C_max, C_min, AUC_0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV C_max, C_min, AUC_0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission.ImplicationsWe found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.