Factors associated with applicant performance on the Saudi Pharmacist Licensure Examination (SPLE).

Background: Limited data are available on factors that are associated with passing rates for the Saudi Pharmacist Licensure Examination (SPLE). The aim of this study is to investigate student characteristics and academic performance characteristics that may predict their success on SPLE. Methods: This was a single-institution retrospective cohort study, which included pharmacy graduates from 2019 to 2021. Demographic, academic, and SPLE data were collected for each graduate. Binary logistic regression was used to explore the association between potential predictors and first-time SPLE pass status. A stepwise regression was then performed to develop multiple logistic models. Results: A total of 494 graduates were included in the study. Females, PharmD graduates, and on-time graduation had higher odds of passing SPLE (P = 0.0065, P = 0.0003, and P < 0.0001, respectively). For each 0.5 increase in GPA, the odds of passing SPLE increase by 3.5 times (OR 3.53; 95 % CI, 2.83-4.42; P < 0.0001). Of the tests taken prior to university admission, the overall high school score, general aptitude test (GAT) score, and qualifying score were significantly associated with higher SPLE first-time pass rates. When multiple logistic regression analysis was performed, GPA and GAT scores were the only significant predictors for higher SPLE first-time pass rates (P < 0.0001 and P = 0.0002, respectively). Conclusion: The current research has shown that there is an association between higher SPLE first-time pass rates and several factors, most importantly the GPA and GAT score. Further research is needed, as it has the potential to inform the decision when reviewing pharmacy admission criteria.

The effect of anti-tuberculosis drug pharmacokinetics on QTc prolongation.

BACKGROUND: Implementation of newer anti-tuberculosis (TB) drugs may prolong the QT interval, increasing the risk of arrythmias and sudden cardiac death. The potential for cardiac adverse events has prompted recommendations for frequent cardiac monitoring during treatment. However, unknowns remain, including the association between drug concentrations and QT interval. METHODS: An observational prospective cohort study design was used. Patients undergoing treatment for drug-resistant TB in Georgia were assessed. Serial blood samples were collected at 4-6 weeks for pharmacokinetics. Electrocardiograms were recommended to be performed monthly. A generalized estimating equation spline model was used to investigate (1) the effect difference between bedaquiline and delamanid, (2) the cumulative effect of number of anti-TB drugs, and (3) the relationship between serum drug concentrations on QTc interval. RESULTS: Among 94 patients receiving either bedaquiline (n = 64) or delamanid (n = 30)-based treatment, most were male (82%), and the mean age was 39 years. The mean maximum QTc increase during the first six months was 37.5 ms (IQR: 17.8-56.8). Bedaquiline- and delamanid-based regimens displayed similar increased mean QTc change from baseline during drug administration (P = 0.12). Increasing number of anti-TB drugs was associated with an increased QTc (P = 0.01), but participants trended back towards baseline after drug discontinuation (P = 0.25). A significant association between AUC, Cmin, Cmax, and increased QTc interval was found for bedaquiline (months 1-6) and levofloxacin (months 1-12). CONCLUSION: Bedaquiline- and delamanid-based regimens and increasing number of QT prolonging agents led to modest increases in the QTc interval with minimal clinical effect.

Comparison of Saudi Pharmacist Licensure Examination (SPLE) Pass Rates by Institution and Applicant Characteristics.

In 2019, the Saudi Pharmacist Licensure Examination (SPLE) was first administered to all pharmacy graduates and served as one of the prerequisites for obtaining a pharmacist license. The objective of this study was to evaluate whether institution and applicant characteristics are associated with first-time SPLE success. Passing status for 2284 SPLE first-time applicants was obtained from online public data for the years 2019 and 2020. The data included applicant sex, institution type (public vs. private), and college establishment year (2006 or earlier vs. after 2006). Overall, the SPLE first-time pass rate in 2020 was significantly higher than in 2019 (98.0 vs. 95.9%; p = 0.0062). Applicants from pharmacy colleges established in or before 2006 had a higher SPLE first-time pass rate, compared to those from pharmacy colleges established after 2006 (98.2 vs. 95.2%; p < 0.0001). The pass rate for male applicants was lower compared to female applicants (95.8 vs. 97.5%; p = 0.0221). The results of logistic regression showed that exam year (2020 vs. 2019), applicant sex (female vs. male), and pharmacy college establishment year (≤2006 vs. >2006) were statistically significant predictors. Further studies are needed in the upcoming years when more cumulative data are available.

Linezolid Exposure Is Associated with Cytopenias in Patients Treated for Multidrug-Resistant Tuberculosis.

Although linezolid is effective for multidrug-resistant TB (MDR-TB) tuberculosis treatment, it is associated with cytopenias after 4 weeks of administration. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in MDR-TB treatment are limited, and concerns about toxicity present barriers to wider implementation. This was a secondary analysis of a prospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015 to 2017. Intensive blood sampling 4 to 6 weeks after treatment initiation with linezolid 600 mg daily was performed for pharmacokinetic (PK) analysis, including linezolid trough concentration (Cmin) and area under the curve from 0 to 24 hours (AUC0-24). Linezolid exposure was defined using literature-reported thresholds. Cytopenias were defined using an NIH adverse event (AE) scale. Logistic regression was used to evaluate the relationship between linezolid exposure and cytopenias. Among 76 patients receiving linezolid in their baseline treatment regimen and who had PK data available, cytopenia AEs occurred in 30 (39.5%) for an incidence rate of 46 per 100 person-years. The median duration of linezolid therapy was 526 days. No patients required dose reduction or interruption due to cytopenias. Median linezolid Cmin was 0.235 mg/L (interquartile range [IQR], 0.069 to 0.529), and median AUC0-24 was 89.6 mg·h/L (IQR, 69.2 to 116.2). Cytopenias were associated with linezolid PK parameters (Cmin > 2 mg/L and AUC0-24 > 160 mg·h/L). Cytopenias occurred frequently with long-term use of linezolid 600 mg/day and were associated with PK parameters but did not result in the need for treatment interruption in the management of a cohort of patients with MDR-TB.

Pharmacogenetic predictors of nevirapine pharmacokinetics in Ghanaian children living with HIV with or without TB coinfection.

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is used in the treatment of human immunodeficiency virus (HIV) infection in children younger than 3 years old. Identifying genetic predictors of NVP pharmacokinetics (PK) in young children is important because inter-individual variability in NVP concentrations contributes to variable treatment response and the information may be used to individualize dosing decisions. We examined the relationship between genetic variations in relevant drug disposition genes and NVP PK parameters in Ghanaian children living with HIV eligible to initiate NVP-based antiretroviral therapy. Participants received NVP plus zidovudine and lamivudine or abacavir and lamivudine twice daily, and those with tuberculosis (TB) coinfection received concurrent anti-TB therapy with NVP. Pharmacokinetic sampling was performed after at least 4 weeks of antiretroviral therapy. Nevirapine minimum concentration (Cmin), area under the concentration-time curve from time 0 to 12 h (AUC0-12h), and apparent clearance (CL/F) were calculated using non-compartmental analysis using Phoenix v8.0 software. Genotyping for CYP2B6, CYP2A6, CYP3A5, ABCB1, NR1I2, and NR1I3 single nucleotide polymorphism (SNPs) was performed by TaqMan® allelic discrimination method. The median (range) NVP dose received was 10 (7-14) mg/kg. Of the 53 participants, the median (range) Cmin was 3.3 (0.0-14.0) mg/L and AUC0-12h was 56.0 (16.7-202.6) mg.hr/L. Using step-wise regression, CYP2B6 rs3745274 and NR1I2 rs6785049 SNPs were independent as well as joint predictors of NVP AUC0-12h, Cmin, and CL/F. We concluded that genotyping for CYP2B6 rs3745274, and the NR1I2 rs6785049 G > A SNP (which encodes the transcriptional factor, pregnane X receptor), could improve prediction of NVP PK for individualized therapy.

Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis.

BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use. OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis. METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored. RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine. CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.

Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia.

Drug development, from preclinical to clinical studies, is a lengthy and complex process. There is an increased interest in the Kingdom of Saudi Arabia (KSA) to promote innovation, research and local content including clinical trials (Phase I-IV). Currently, there are over 650 registered clinical trials in Saudi Arabia, and this number is expected to increase. An important part of drug development and clinical trials is to assure the safe and effective use of drugs. Clinical pharmacology plays a vital role in informed decision making during the drug development stage as it focuses on the effects of drugs in humans. Disciplines such as pharmacokinetics, pharmacodynamics and pharmacogenomics are components of clinical pharmacology. It is a growing discipline with a range of applications in all phases of drug development, including selecting optimal doses for Phase I, II and III studies, evaluating bioequivalence and biosimilar studies and designing clinical studies. Incorporating clinical pharmacology in research as well as in the requirements of regulatory agencies will improve the drug development process and accelerate the pipeline. Clinical pharmacology is also applied in direct patient care with the goal of personalizing treatment. Tools such as therapeutic drug monitoring, pharmacogenomics and model informed precision dosing are used to optimize dosing for patients at an individual level. In KSA, the science of clinical pharmacology is underutilized and we believe it is important to raise awareness and educate the scientific community and healthcare professionals in terms of its applications and potential. In this review paper, we provide an overview on the use and applications of clinical pharmacology in both drug development and clinical care.

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

PURPOSE: This 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. METHODS: A 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 Cmax and AUC estimates for all INH dosages. FINDINGS: Ninety studies were included in this systematic review. TB status significantly affected the INH Cmax and AUC estimates. In healthy volunteers, the dose-normalized INH Cmax and AUC were statistically higher than those of patients with TB. No significant differences were found in dose-normalized Cmax 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 Cmax and AUC of pediatric patients with TB and TB/HIV with their respective adult counterparts. Dose-normalized INH Cmax and AUC in patients with fast and intermediate NAT2 were significantly lower than in patients with slow NAT2. IMPLICATIONS: The 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.

Population Pharmacokinetics of Linezolid in Tuberculosis Patients: Dosing Regimen Simulation and Target Attainment Analysis.

The prolonged treatment duration for multidrug-resistant tuberculosis (MDR-TB) makes linezolid dosing difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid across different MIC values. Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used an fAUC (area under the unbound drug concentration-time curve)/MIC ratio of >119 as the PK/pharmacodynamic (PD) target and minimum (trough) concentrations of drug (Cmins) of 2 and 7 mg/liter as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%. A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kg. Eighty-one percent had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/liter for a total daily dose of 300 mg, while daily doses of 450 to 600 mg and 900 to 1,200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/liter, respectively. The probability of achieving a Cmin of ≤2 mg/liter was higher when the dose was given at once than when dividing it into 2 doses. Linezolid at a daily dose of 300 mg may not be optimal. We predicted an excellent and comparable efficacy of linezolid using total daily doses of 900 and 1,200 mg for MICs of ≤0.5 mg/liter but with the potential for more toxicity than with 600 mg daily. The increase in Cmin was noticeable when the daily dose was divided and may incur greater toxicity.

Variable linezolid exposure and response and the role of therapeutic drug monitoring: Case series.

Two patients with normal renal function, yet each showed unexpected, supra- and subtherapeutic linezolid plasma concentrations resulting in toxicity and ineffective therapy, respectively. TDM helps to early identify and correct such excursions.

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis.

Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250 mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h-1; elimination rate constant, 0.69 (0.46) h-1; volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500 mg or more was needed for ≥90% attainment of the 1.0-log kill target at a MIC of 1 mg/liter, and 2,250 mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5 mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting the current recommendations for ETA deprioritization.

Meropenem, Cefepime, and Piperacillin Protein Binding in Patient Samples.

BACKGROUND: The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the available therapeutic options is required. Beta-lactams are time-dependent antibiotics and their efficacy is determined by the amount of time the free concentration remains above the minimum inhibitory concentration. Therefore, the aim of this study was to assess the extent and variability of protein binding for meropenem, cefepime, and piperacillin. METHODS: Plasma samples for the analysis of meropenem, cefepime, and piperacillin were collected from patients admitted to a tertiary care hospital as part of the standard care. The bound and unbound drug fractions in the samples were separated by ultrafiltration. Validated liquid chromatography-tandem mass spectrometry assays were used to quantify the total and free plasma concentrations, and the protein binding was determined. RESULTS: Samples from 95 patients were analyzed. The median (range) age of patients was 56 years (17-87) and the median (range) body mass index was 25.7 kg/m (14.7-74.2). Approximately 59% of the patients were men. The median (range) unbound fraction (fu) was 62.5% (41.6-99.1) for meropenem, 61.4% (51.6-99.2) for cefepime, and 48.3% (39.4-71.3) for piperacillin. In the bivariate analysis, as the total meropenem concentration increased, the fu increased (r = 0.37, P = 0.045). A decrease in piperacillin fu was observed as the albumin concentration increased (r = -0.56, P = 0.005). CONCLUSIONS: The average fu values were lower than those reported in the literature. There was also a large variability in fu; hence, it should be considered when managing patients administered with these drugs through direct measurements of free drug concentrations.

A Pharmacology Perspective of Simultaneous Tuberculosis and Hepatitis C Treatment.

Tuberculosis (TB) and hepatitis C virus (HCV) infection are both major public health problems. Despite high rates of co-infection there is scarce literature addressing the convergence of the two diseases. One particularly unexplored area is the potential for simultaneous treatment of TB and HCV which would allow for leveraging an extensive global TB treatment infrastructure to help scale up HCV treatment. We review the drug metabolism of anti-TB and HCV drugs and the known and potential drug-drug interactions between recommended HCV regimens and individual anti-TB drugs. Rifampin is the only anti-TB drug to have been formally studied for potential drug interactions with anti-HCV direct-acting antivirals (DAAs) and existing data precludes these combinations. However, based on known pathways of drug metabolism and enzyme effects, the combination of HCV DAA regimens with all other anti-TB drugs may be feasible. Pharmacokinetic studies are needed next to help move co treatment regimens forward for clinical use among patients coinfected with TB and HCV.

Effect of First-Line Antituberculosis Therapy on Nevirapine Pharmacokinetics in Children Younger than Three Years Old.

Nevirapine-based antiretroviral therapy (ART) is one of the limited options in HIV-infected children younger than 3 years old (young children) with tuberculosis (TB) coinfection. To date, there are insufficient data to recommend nevirapine-based therapy during first-line antituberculosis (anti-TB) therapy in young children. We compared nevirapine pharmacokinetics (PK) in HIV-infected young children with and without TB coinfection. In the coinfected group, nevirapine PK was evaluated while on anti-TB therapy and after completing an anti-TB therapy regimen. Of 53 participants, 23 (43%) had TB-HIV coinfection. While the mean difference in nevirapine PK parameters between the two groups was not significant (P > 0.05), 14/23 (61%) of the children with TB-HIV coinfection and 9/30 (30%) with HIV infection had a nevirapine minimum concentration (Cmin) below the proposed target of 3.0 mg/liter (P = 0.03). In multivariate analysis, anti-TB therapy and the CYP2B6 516G>T genotype were joint predictors of nevirapine PK parameters. Differences in nevirapine PK parameters between the two groups were significant in children with CYP2B6 516GG but not the GT or TT genotype. Among 14 TB-HIV-coinfected participants with paired data, the geometric mean Cmin and area under the drug concentration-time curve from time zero to 12 h (AUC0-12) were about 34% lower when patients were taking anti-TB therapy, while the nevirapine apparent oral clearance (CL/F) was about 45% higher. While the induction effect of anti-TB therapy on nevirapine PK in our study was modest, the CYP2B6 genotype-dependent variability in the TB drug regimen effect would complicate any dose adjustment strategy in young children with TB-HIV coinfection. Alternate ART regimens that are more compatible with TB treatment in this age group are needed. (This study has been registered at ClinicalTrials.gov under identifier NCT01699633.).

Population pharmacokinetics of efavirenz in HIV and TB/HIV coinfected children: the significance of genotype-guided dosing.

OBJECTIVES: The current WHO weight-based dosing recommendations for efavirenz result in a wide variability of drug exposure in children. Our objectives are to characterize the effects of rifampicin- and isoniazid-containing anti-TB therapy and CYP2B6 activity on efavirenz concentrations in children, using non-linear mixed-effects modelling. METHODS: This is a pharmacokinetic (PK) substudy of a prospective study that examined the interactions between anti-TB therapy and efavirenz in HIV-infected children with and without TB. PK samples were obtained 4 weeks after starting efavirenz (PK1) and repeated 4 weeks after completing TB therapy (PK2) in TB/HIV coinfected patients. Drug concentrations were measured using LC-MS/MS. Composite CYP2B6 516/983/15582 genotype was determined. Population PK modelling was performed in Monolix. Simulations were performed to obtain the predicted mid-dose concentrations (C12). RESULTS: One hundred and five HIV-infected Ghanaian children (46 with TB/HIV) were included. The median age and weight were 7 years and 19 kg. The efavirenz concentrations over time were adequately described using a one-compartment model. Weight, composite CYP2B6 genotype and PK visit had a significant influence on the PK parameters, while TB therapy had no significant effect. Simulations showed adequate C12 for intermediate composite CYP2B6 metabolizers only. CONCLUSIONS: Our model showed that rifampicin- and isoniazid-containing anti-TB therapy does not influence efavirenz PK parameters. On the other hand, it describes the effect of efavirenz autoinduction after completing TB treatment. In addition, dosing efavirenz in children based only on weight results in a large variability in drug exposure. We propose dose adjustments for slow and extensive composite CYP2B6 metabolizers.

Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection.

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis.

Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on cycloserine in tuberculosis (TB) patients. We pooled several studies into a large PK data set to estimate the population PK parameters for cycloserine in TB patients. We also performed simulations to provide insight into optimizing the dosing of cycloserine. TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC of ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA. Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA were achieved as the total daily dose was increased. The highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/liter. For MICs of >16 mg/liter, doses of at least 500 mg three times daily or 750 mg twice daily were needed. In conclusion, the current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs of >16mg/liter. Further studies are needed regarding the efficacy and tolerability of daily doses of >1,000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimizing exposure, which can potentially reduce adverse drug effects.