Clinical pharmacokinetics of quinine and its relationship with treatment outcomes in children, pregnant women, and elderly patients, with uncomplicated and complicated malaria: a systematic review.

BACKGROUND: Standard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine. METHODS: Web of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values. RESULTS: Twenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups. CONCLUSIONS: The recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered.

ß-Eudesmol induces the expression of apoptosis pathway proteins in cholangiocarcinoma cell lines.

BACKGROUND: Cholangiocarcinoma (CCA) is a neglected disease prevalent in developing countries with high burden and mortality rate, and there is no effective treatment. We aimed to investigate ß-eudesmol molecular target of action in human CCA cell lines using the selected key molecules of apoptotic pathways. MATERIALS AND METHODS: Two CCA cell lines (HuH28 and HuCCT1) were assessed at different time points after ß-eudesmol treatment for mRNA and protein expression profiles of caspase-3, -8, -9, p53, p21, Bcl-2, and Bax by real-time polymerase chain reaction and western blot, respectively. RESULTS: ß-eudesmol induced expressions of p21 and p53 in mRNA/protein level in HuH28 and HuCCT1 cells. These CCA cells also expressed caspase-3, -8, -9 and bax (mRNA and/or protein level) among others after ß-eudesmol treatment indicating its role in both intrinsic and extrinsic caspase-dependent apoptotic pathways. CONCLUSION: The study demonstrated that ß-eudesmol induced the expression of apoptosis pathway proteins, suggesting its potential role in promoting the caspase-dependent apoptotic pathway, and induction of the cell cycle arrest in CCA cell lines. ß-eudesmol can be considered as a potential compound for further investigation as an anti-CCA agent.

Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review.

PURPOSE: Physiologically based pharmacokinetic (PBPK) modeling, a mathematical modeling approach which uses a pharmacokinetic model to mimick human physiology to predict drug concentration-time profiles, has been used for the discover and development of drugs in various fields, including oncology, since 2000. There have been a few general review articles on the utilization of PBPK in the development of oncology drugs, but these do not include an evaluation of model prediction accuracy. We therefore conducted a systematic review to define the accuracy of PBPK model prediction and its utility throughout all the developmental phases of oncology drugs. METHODS: A systematic search was performed in the PubMed, PubMed Central and Cochrane Library databases from 1980 to February 2017 for articles (1) written in English, (2) focused on oncology or antineoplastic or anticancer drugs, tumor or cancer or anticancer drugs listed in the U.S. National Institutes of Health and (3) involving a PBPK model. The absolute-average-folding-errors (AAFEs) of the area under the curve (AUC) between predicted and observed values in each article were calculated to assess model prediction accuracy. RESULTS: Of the 2341 articles initially identified by our search of the databases, 40 were included in the review analysis. These articles reported on six types of studies, i.e. in vivo (n = 4), first-in-human (n = 5), phase II/III clinical trials (n = 9), organ impairment (n = 3), pediatrics (n = 4) and drug-drug interactions (n = 15). AAFEs of the predicted AUC for all groups of studies were within 1.3-fold of each other despite variations in experimental methodologies. CONCLUSION: PBPK modeling is a potential tool which can be effectively applied throughout all phases of oncology drug development. The number of experimental animals and human participants enrolled in the studies can be reduced using PBPK modeling and PBPK-population-PK modeling. The limited number of publications of unsuccessful model application to date may contribute to bias toward the usefulness of modeling.

Interleukin-6 and Lymphocyte-to-Monocyte Ratio Indices Identify Patients with Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a fatal biliary tract cancer with a dismal prognosis due to ineffective diagnostic tools with limited clinical utility. This study investigated peripheral blood indices and cytokine levels to diagnose iCCA. METHODS: Blood samples were collected from healthy subjects (n = 48) and patients with advanced-stage iCCA (n = 47) during a phase I and then phase II trial, respectively. Serum cytokines were measured using a flow cytometer. The peripheral blood indices were estimated based on laboratory data. Multi-linear regression analysis was applied, followed by a probability transformation. The cut-off value and model accuracy were determined using the receiver operating curve (ROC) and the area under the curve (AUC). RESULTS: The interleukin-6 (IL6) and lymphocyte-to-monocyte ratio (LMR) were potential predictors of iCCA [AUC = 0.91 (0.85-0.97) and 0.81 (0.68-0.93); sensitivity = 0.70 and 0.91; specificity = 0.91 and 0.85, respectively]. Patients with IL6 concentrations higher than 11.635 pg/mL (OR = 23.33, p < 0.001) or LMR lower than 7.2 (OR = 58.08, p < 0.001) are at risk of iCCA development. Patients with IL6 levels higher than 21.83 pg/mL, between 15.95 and 21.83 pg/mL, between 8.8 and 15.94 pg/mL, and lower than 8.8 pg/mL were classified as very high-, high-, intermediate-, and low-risk, respectively. Patients with an LMR between 1 and 3.37, 3.38 and 5.76, 5.77 and 7.18, and higher than 7.18 were classified as very high-, high-, intermediate-, and low-risk, respectively. CONCLUSIONS: LMR is recommended for iCCA screening since the estimation is based on a routine laboratory test, which is available in most hospitals.

Pharmacokinetic Analysis of Prognostic Factors in Patients With Advanced-Stage Intrahepatic Cholangiocarcinoma Following the Administration of Capsule Formulation of the Standardized Extract of Atractylodes lancea (Thunb) DC.

BACKGROUND: A statistical model is essential in determining the appropriate predictive indicators for therapies in many types of cancers. Predictors have been compared favorably to the traditional systems for many cancers. Thus, this study has been proposed as a new standard approach. A recent study on the clinical efficacy of Atractylodes lancea (Thunb) DC. (AL) revealed the higher clinical benefits in patients with advanced-stage intrahepatic cholangiocarcinoma (ICC) treated with AL compared with standard supportive care. We investigated the relationships between clinical efficacy and pharmacokinetic parameters of serum bioactivity of AL and its active constituent atractylodin and determined therapeutic ranges. METHODS: Group 1 of advanced-stage ICC patients received daily doses of 1000 mg of standardized extract of the capsule formulation of AL (CMC-AL) for 90 days. Group 2 received daily doses of 1000 mg of CMC-AL for 14 days, followed by 1500 mg for 14 days, and 2000 mg for 62 days. Group 3 (control group) received palliative care. Cox proportional hazard model and Receiver Operating Characteristic (ROC) were applied to determine the cut-off values of AUC0-inf, Cmax, and Cavg associated with therapeutic outcomes. Number needed to treat (NNT) and relative risk (RR) were also applied to determine potential predictors. RESULTS: The AUC0-inf of total AL bioactivity of >96.71 µg hour/ml was identified as a promising predictor of disease prognosis, that is, progression-free survival (PFS) and disease control rate (DCR). Cmax of total AL bioactivity of >21.42 was identified as a predictor of the prognosis of survival. The therapeutic range of total AL bioactivity for PFS and DCR is 14.48 to 65.8 µg/ml, and for overall survival is 10.97 to 65.8 µg/ml. Conclusions: The predictors of ICC disease prognosis were established based on the pharmacokinetics of total AL bioactivity. The information could be exploited to improve the clinical efficacy of AL in patients with advanced-stage ICC. These predictors will be validated in a phase 2B clinical study. TRIAL REGISTRATION: TCTR20210129007 (TCTR: www.clinicaltrials.in.th).

Prediction of improved antimalarial chemotherapy of artesunate-mefloquine in combination with mefloquine sensitive and resistant Plasmodium falciparum malaria.

BACKGROUND: Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment. OBJECTIVE: This study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant P. falciparum malaria. METHODS: Data collected during 2008-2009 from 124 patients with uncomplicated P. falciparum malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients' adherence and parasite biomass. RESULTS: The developed PK/PD models well described with clinically observed data. For mefloquine-resistant P. falciparum, a three-day standard regimen of artesunate-mefloquine is suitable (>50% efficacy) only when the level of parasite sensitivity was < 1.5-fold of the cut-off level (IC50 < 36 nM). For mefloquine-sensitive parasite with IC50 < 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC50 of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C336h (>408 ng.mL-1) or Cmax/IC50 (>130.1 g.m/M), and Cmax/IC50 (>381.2 g.m/M), respectively. CONCLUSIONS: Clinical use of a three-day standard artesunate-mefloquine is suitable only when the IC50 of P. falciparum isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC50 is lower than 23.19 nM.

In Silico Prediction of Andrographolide Dosage Regimens for COVID-19 Treatment.

Andrographolide (APE) has been used for COVID-19 treatment in various clinical settings in South-East Asia due to its benefits on reduction of viral clearance and prevention of disease progression. However, the limitation of APE clinical use is the high incidence of adverse events. The objective of this study was to find the optimal dosage regimens of APE for COVID-19 treatment. The whole-body physiologically-based pharmacokinetic (PBPK) models were constructed using data from the published articles and validated against clinical observations. The inhibitory effect of APE was determined for the potency of drug efficacy. For prevention of pneumonia, multiple oral doses such as 120[Formula: see text]mg for three doses, followed by 60[Formula: see text]mg three times daily for 4 consecutive days, or 200[Formula: see text]mg intravenous infusion at the rate of 20 mg/h once daily is advised in patients with mild COVID-19. For prevention of pneumonia and reduction of viral clearance time, the recommended dosage regimen is 500[Formula: see text]mg intravenous infusion at the rate of 25[Formula: see text]mg/h once daily in patients with mild-to-moderate COVID-19. One hundred virtual populations (50 males and 50 females) were simulated for oral and intravenous infusion formulations of APE. The eligible PBPK/PD models successfully predicted optimal dosage regimens and formulations of APE for prevention of disease progression and/or reduction of viral clearance time. Additionally, APE should be co-administered with other antiviral drugs to enhance therapeutic efficacy for COVID-19 treatment.

Physiologically-Based Pharmacokinetic Modeling for Optimal Dosage Prediction of Quinine Coadministered With Ritonavir-Boosted Lopinavir.

The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800 mg t.i.d. in patients with malaria with HIV infection, 648 mg b.i.d. in chronic renal failure, 648 mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324 mg b.i.d.), and 648 mg t.i.d. in CYP3A4 polymorphism).