Tuberculosis (TB) is the world’s second leading infectious killer. Cases of multidrug-resistant (MDR-TB) and extremely drug-resistant (XDR-TB) have increased globally. Therapeutic drug monitoring (TDM) remains a standard clinical technique for using plasma drug concentrations to determine dose. For TB patients, TDM provides objective information for the clinician to make informed dosing decisions. Some patients are slow to respond to treatment, and TDM can shorten the time to response and to treatment completion. Normal plasma concentration ranges for the TB drugs have been defined. For practical reasons, only one or two samples are collected post-dose. A 2-h post-dose sample approximates the peak serum drug concentration (C_max) for most TB drugs. Adding a 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampicin is stable for more than 6 h under these conditions. Since our 2002 review, several papers regarding TB drug pharmacokinetics, pharmacodynamics, and TDM have been published. Thus, we have better information regarding the concentrations required for effective TB therapy. In vitro and animal model data clearly show concentration responses for most TB drugs. Recent studies emphasize the importance of rifamycins and pyrazinamide as sterilizing agents. A strong argument can be made for maximizing patient exposure to these drugs, short of toxicity. Further, the very concept behind ‘minimal inhibitory concentration’ (MIC) implies that one should achieve concentrations above the minimum in order to maximize response. Some, but not all clinical data are consistent with the utility of this approach. The low ends of the TB drug normal ranges set reasonable ‘floors’ above which plasma concentrations should be maintained. Patients with diabetes and those infected with HIV have a particular risk for poor drug absorption, and for drug–drug interactions. Published guidelines typically describe interactions between two drugs, whereas the clinical situation often is considerably more complex. Under ‘real–life’ circumstances, TDM often is the best available tool for sorting out these multi-drug interactions, and for providing the patient safe and adequate doses. Plasma concentrations cannot explain all of the variability in patient responses to TB treatment, and cannot guarantee patient outcomes. However, combined with clinical and bacteriological data, TDM can be a decisive tool, allowing clinicians to successfully treat even the most complicated TB patients.

The aim of the present study was to investigate the potential effect of thymoquinone (TQ) on the metabolic activity of four major drug metabolizing enzymes in human liver microsomes, namely cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6 and CYP3A4. The inhibition of CYP enzymatic activities by TQ was evaluated by incubating typical substrates (phenacetin for CYP1A2, tolbutamide for CYP2C9, dextromethorphan for CYP2D6, and testosterone for CYP3A4) with human liver microsomes and NADPH in the absence or presence of TQ (1, 10 and 100 µM). The respective metabolite of the substrate that was formed was measured by HPLC. Results of the presented study presented that the metabolic activities of all the investigated CYP enzymes, viz. CYP1A2, CYP2C9, CYP2D6 and CYP3A4, were inhibited by TQ. At 1 µM TQ, CYP2C9 enzyme activity was maximally inhibited by 46.35%, followed by CYP2D6 (20.26%) > CYP1A2 (13.52%) > CYP3A4 (12.82%). However, at 10 µM TQ, CYP2C9 enzyme activity was maximally inhibited by 69.69%, followed by CYP3A4 (23.59%) > CYP1A2 (23.51%) > CYP2D6 (11.42%). At 100 µM TQ, CYP1A2 enzyme activity was maximally inhibited by 81.92%, followed by CYP3A4 (79.24%) > CYP2C9 (69.22%) > CYP2D6 (28.18%). The IC₅₀ (mean ± SE) values for CYP1A2, CYP2C9, CYP2D6 and CYP3A4 inhibition were 26.5 ± 2.9 µM, 0.5 ± 0.4 µM, >500 µM and 25.2 ± 3.1 µM, respectively. These findings suggest that there is a high probability of drug interactions resulting from the co-administration of TQ or herbs containing TQ with drugs that are metabolized by the CYP enzymes, particularly CYP2C9.

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.

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration ( C _max ) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C _max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC _0–24 ) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution ( V / F ) than men, and both clearance (CL/ F ) and V / F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C _max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.