Pharmaceuticals

Research

12 pages, 1314 KiB

Open AccessArticle

Drug–Drug Interactions between Tamsulosin and Mirabegron in Healthy Individuals Do Not Affect Pharmacokinetics and Hemodynamic Parameters Significantly

by Wonsuk Shin, A-Young Yang, Hyounggyoon Yoo and Anhye Kim

Pharmaceuticals 2023, 16(10), 1457; https://doi.org/10.3390/ph16101457 - 13 Oct 2023

Cited by 1 | Viewed by 1520

Abstract

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, substantially affecting quality of life. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining [...] Read more.

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, substantially affecting quality of life. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, three-period, drug–drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), or a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron was reduced by approximately 17% when administered with tamsulosin. No clinically significant changes in the safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug–drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination could be a promising treatment option for patients with OAB. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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11 pages, 1820 KiB

Open AccessArticle

A Comparative Pharmacokinetic Study of Fexuprazan 10 mg: Demonstrating Bioequivalence with the Reference Formulation and Evaluating Steady State

by Wonsuk Shin, A-Young Yang, Hyung Park, Hyejung Lee, Hyounggyoon Yoo and Anhye Kim

Pharmaceuticals 2023, 16(8), 1141; https://doi.org/10.3390/ph16081141 - 11 Aug 2023

Cited by 1 | Viewed by 4562

Abstract

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric-acid-related diseases. Although the effectiveness of the recent formulation fexuprazan 10 mg has been demonstrated in Phase 3 clinical trials, data on the pharmacokinetics (PKs) of administering fexuprazan 10 mg twice daily at a [...] Read more.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric-acid-related diseases. Although the effectiveness of the recent formulation fexuprazan 10 mg has been demonstrated in Phase 3 clinical trials, data on the pharmacokinetics (PKs) of administering fexuprazan 10 mg twice daily at a 12 h interval are lacking. Moreover, it is imperative to ensure the bioequivalence of the new formulation with the previously approved 40 mg formulation. This study evaluated the pharmacokinetics (PKs) of the single- and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy participants (Part 1) and investigated their bioequivalence with 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, one-sequence, two-period design and eight participants, while Part 2 comprised a single-dose, 2 × 2 crossover design and 24 participants. In Part 1, in Periods 1 and 2, participants received single and multiple doses (twice daily) of fexuprazan 10 mg, respectively. The maximum plasma concentration (C_max) area under the concentration–time curve from 0 to 12 h (AUC_0–12h) of the multiple-dose participants was approximately double that of the single-dose participants. In Part 2, the geometric mean ratios (90% confidence intervals) for C_max and AUC from zero to the time of the last quantifiable concentration (AUC_last) of the use of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, meeting the bioequivalence criteria. Favorable PKs were observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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12 pages, 1290 KiB

Open AccessArticle

Application of the Population Pharmacokinetics Model-Based Approach to the Prediction of Drug–Drug Interaction between Rivaroxaban and Carbamazepine in Humans

by Lien Thi Ngo, Hwi-yeol Yun and Jung-woo Chae

Pharmaceuticals 2023, 16(5), 684; https://doi.org/10.3390/ph16050684 - 2 May 2023

Cited by 1 | Viewed by 2706

Abstract

Rivaroxaban (RIV) is one of the direct oral anticoagulants used to prevent and treat venous and arterial thromboembolic events. Considering the therapeutic indications, RIV is likely to be concomitantly administered with various other drugs. Among these is carbamazepine (CBZ), one of the recommended [...] Read more.

Rivaroxaban (RIV) is one of the direct oral anticoagulants used to prevent and treat venous and arterial thromboembolic events. Considering the therapeutic indications, RIV is likely to be concomitantly administered with various other drugs. Among these is carbamazepine (CBZ), one of the recommended first-line options to control seizures and epilepsy. RIV is a strong substrate of cytochrome P450 (CYP) enzymes and Pgp/BCRP efflux transporters. Meanwhile, CBZ is well known as a strong inducer of these enzymes and transporters. Therefore, drug–drug interaction (DDI) between CBZ and RIV is expected. This study aimed to predict the DDI profile of CBZ and RIV in humans by using a population pharmacokinetics (PK) model-based approach. We previously investigated the population PK parameters of RIV administered alone or with CBZ in rats. In this study, those parameters were extrapolated from rats to humans by using simple allometry and liver blood flow scaling, and then applied to back-simulate the PK profiles of RIV in humans (20 mg RIV per day) used alone or with CBZ (900 mg CBZ per day). Results showed that CBZ significantly reduced RIV exposure. The AUC_inf and C_max of RIV decreased by 52.3% and 41.0%, respectively, following the first RIV dose, and by 68.5% and 49.8% at the steady state. Therefore, the co-administration of CBZ and RIV warrants caution. Further studies investigating the extent of DDIs between these drugs should be conducted in humans to fully understand their safety and effects. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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12 pages, 10551 KiB

Open AccessArticle

Changes in Pharmacokinetics and Pharmacodynamics of Losartan in Experimental Diseased Rats Treated with Curcuma longa and Lepidium sativum

by Abdul Ahad, Mohammad Raish, Ibrahim Abdelsalam Abdelrahman, Yousef A. Bin Jardan, Mohd Aftab Alam, Abdullah M. Al-Mohizea and Fahad I. Al-Jenoobi

Pharmaceuticals 2023, 16(1), 33; https://doi.org/10.3390/ph16010033 - 26 Dec 2022

Cited by 6 | Viewed by 3035

Abstract

The current study investigated “pharmacodynamics and pharmacokinetics interactions” of losartan with Curcuma longa (CUR) and Lepidium sativum (LS) in hypertensive rats. Hypertension was induced by oral administration of L-NAME (40 mg/kg) for two weeks. Oral administration of CUR or LS shows some substantial [...] Read more.

The current study investigated “pharmacodynamics and pharmacokinetics interactions” of losartan with Curcuma longa (CUR) and Lepidium sativum (LS) in hypertensive rats. Hypertension was induced by oral administration of L-NAME (40 mg/kg) for two weeks. Oral administration of CUR or LS shows some substantial antihypertensive activity. The systolic blood pressure (SBP) of hypertensive rats was decreased by 7.04% and 8.78% 12 h after treatment with CUR and LS, respectively, as compared to rats treated with L-NAME alone. LS and CUR display the ability to potentiate the blood pressure-lowering effects of losartan in hypertensive rats. A greater decrease in SBP, by 11.66% and 13.74%, was observed in hypertensive rats treated with CUR + losartan and LS + losartan, respectively. Further, both the investigated herbs, CUR and LS, caused an increase in plasma concentrations of losartan in hypertensive rats. The AUC_0-t, AUC_0-inf and AUMC_0-inf of losartan were increased by 1.25-fold, 1.28-fold and 1.09-fold in hypertensive rats treated with CUR + losartan. A significant (p < 0.05) increase in AUC_0-t (2.41-fold), AUC_0-inf (3.86-fold) and AUMC_0-inf (8.35-fold) of losartan was observed in hypertensive rats treated with LS + losartan. The present study affirms that interactions between CUR or LS with losartan alter both “pharmacokinetics and pharmacodynamics” of the drug. Concurrent administration of losartan with either CUR or LS would require dose adjustment and intermittent blood pressure monitoring for clinical use in hypertensive patients. Additional investigation is necessary to determine the importance of these interactions in humans and to elucidate the mechanisms of action behind these interactions. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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10 pages, 2557 KiB

Open AccessArticle

Aspartames Alter Pharmacokinetics Parameters of Erlotinib and Gefitinib and Elevate Liver Enzymes in Wistar Rats

by Hajer AlRasheed, Aliyah Almomen, Haya I. Aljohar, Maria Arafah, Rana Y. Almotawa, Manal A. Alossaimi and Nourah Z. Alzoman

Pharmaceuticals 2022, 15(11), 1400; https://doi.org/10.3390/ph15111400 - 14 Nov 2022

Cited by 1 | Viewed by 2754

Abstract

Background: Erlotinib (ERL) and gefitinib (GEF) are extensively metabolized by CYP450 enzymes. Aspartame (ASP), an artificial sweetener, induces CYP2E1 and CYP3A2 enzymes in the brain and could increase liver enzymes. In this work, the influence of ASP on the pharmacokinetics (PK) of ERL [...] Read more.

Background: Erlotinib (ERL) and gefitinib (GEF) are extensively metabolized by CYP450 enzymes. Aspartame (ASP), an artificial sweetener, induces CYP2E1 and CYP3A2 enzymes in the brain and could increase liver enzymes. In this work, the influence of ASP on the pharmacokinetics (PK) of ERL and GEF in Wistar rats was evaluated. Methods: The PKs of ERL and GEF were evaluated after receiving 175 mg/kg or 1000 mg/kg of ASP for four weeks using UPLC-MS/MS. Levels of liver enzymes after four weeks of ASP consumption were also evaluated. Results: ASP 175 mg/kg was able to significantly alter levels of C_max (36% increase for ERL, 38% decrease for GEF), AUC_0–72 (205% increase for ERL, 41% increase for GEF), and AUC_0–∞ (112% increase for ERL, 14% increase for GEF). Moreover, ASP 175 mg/kg decreased the apparent oral clearance ERL and GEF by 58% and 13%, respectively. ASP 1000 mg/kg increased C_max of ERL by 159% and decreased GEF’s C_max by and 73%. Both AUC_0–72 and AUC_0–∞ were increased by ASP 1000 for ERL and decreased for GEF. CL/F decreased by 64% for ERL and increased by 38.8% for GEF. Moreover, data indicated that ASP significantly increased levels of liver enzymes within two weeks of administration. Conclusions: Although ASP 175 and 1000 mg/kg alter ERL and GEF PKs parameters, ASP 1000 mg/kg has the highest impact on most parameters. ASP 1000 mg/kg also can significantly increase activities of liver enzymes indicating the possibility of inducing liver injury. Therefore, it might be of clinical importance to avoid the administration of aspartame containing products while on ERL or GEF therapy. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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26 pages, 5371 KiB

Open AccessArticle

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

by Junbo Zhu, Yabin Duan, Delong Duo, Jianxin Yang, Xue Bai, Guiqin Liu, Qian Wang, Xuejun Wang, Ning Qu, Yang Zhou and Xiangyang Li

Pharmaceuticals 2022, 15(10), 1303; https://doi.org/10.3390/ph15101303 - 21 Oct 2022

Cited by 7 | Viewed by 2878

Abstract

(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs [...] Read more.

(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs are limited. (2) Methods: The aim of this study was to evaluate the pharmacokinetics of nifedipine, bosentan, simvastatin, sildenafil, and their respective main metabolites, dehydronifedipine, hydroxybosentan, simvastatin hydroxy acid, and N-desmethyl sildenafil, in rats exposed to high-altitude hypoxia. Additionally, the protein and mRNA expression of cytochrome P450 3A1 (CYP3A1), a drug-metabolizing enzyme, were examined. (3) Results: There were significant changes in the pharmacokinetic properties of the drugs in rats exposed to high-altitude hypoxia, as evidenced by an increase in the area under the curve (AUC) and the half-life (t_1/2z) and a decrease in total plasma clearance (CL_z/F). However, most of these changes were reversed when the rats returned to a normoxic environment. Additionally, there was a significant decrease in CYP3A1 expression in rats exposed to high-altitude hypoxia at both the protein and mRNA levels. (4) Conclusions: High-altitude hypoxia suppressed the metabolism of the drugs, indicating that the pharmacokinetics of the drugs should be re-examined, and the optimal dose should be reassessed in patients living in high-altitude areas. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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11 pages, 1905 KiB

Open AccessArticle

Stability Study, Quantification Method and Pharmacokinetics Investigation of a Coumarin–Monoterpene Conjugate Possessing Antiviral Properties against Respiratory Syncytial Virus

by Arina G. Nemolochnova, Artem D. Rogachev, Olga P. Salnikova, Tatyana M. Khomenko, Konstantin P. Volcho, Olga I. Yarovaya, Alina V. Fatianova, Andrey G. Pokrovsky and Nariman F. Salakhutdinov

Pharmaceuticals 2022, 15(9), 1158; https://doi.org/10.3390/ph15091158 - 18 Sep 2022

Cited by 5 | Viewed by 2129

Abstract

The stability of a new coumarin derivative, agent K-142, bearing α-pinene residue and possessing antiviral activity against respiratory syncytial virus (RSV) was studied in whole mice blood in vitro, and a method for its quantification in this matrix was developed and validated. The [...] Read more.

The stability of a new coumarin derivative, agent K-142, bearing α-pinene residue and possessing antiviral activity against respiratory syncytial virus (RSV) was studied in whole mice blood in vitro, and a method for its quantification in this matrix was developed and validated. The sample preparation method was precipitation of whole blood with a mixture of 0.2 M ZnSO₄ with MeOH (2:8 v/v) containing 2-adamantylamine hydrochloride as an internal standard (IS). Analysis was carried out by HPLC-MS/MS using reversed phase chromatography and a triple quadrupole mass spectrometer 6500 QTRAP (SCIEX) in multiple reaction monitoring (MRM) mode. The transitions 351.2 → 217.1 Da and 152.2 → 93.1/107.2 Da were monitored for K-142 and the IS, respectively. The method was validated in terms of selectivity, calibration curve, LLOQ, accuracy and precision, stability, recovery and carry over. The developed method was used for a pharmacokinetics study of the compound after its oral administration to mice at a dose of 20 mg/kg. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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11 pages, 650 KiB

Open AccessArticle

Pharmacokinetic Interaction between Atorvastatin and Omega-3 Fatty Acid in Healthy Volunteers

by Jae Hoon Kim, Jung Sunwoo, Ji Hye Song, Yu-Bin Seo, Won Tae Jung, Kyu-Yeol Nam, YeSeul Kim, Hye Jung Lee, JungHa Moon, Jin-Gyu Jung and Jang Hee Hong

Pharmaceuticals 2022, 15(8), 962; https://doi.org/10.3390/ph15080962 - 3 Aug 2022

Cited by 4 | Viewed by 3216

Abstract

The interaction between statins and omega-3 fatty acids remains controversial. The aim of this phase 1 trial was to evaluate the pharmacokinetics of drug-drug interaction between atorvastatin and omega-3 fatty acids. Treatments were once-daily oral administrations of omega-3 (4 g), atorvastatin (40 mg), [...] Read more.

The interaction between statins and omega-3 fatty acids remains controversial. The aim of this phase 1 trial was to evaluate the pharmacokinetics of drug-drug interaction between atorvastatin and omega-3 fatty acids. Treatments were once-daily oral administrations of omega-3 (4 g), atorvastatin (40 mg), and both for 14 days, 7 days, and 14 days, respectively, with washout periods. The concentrations of atorvastatin, 2-OH-atorvastatin, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were determined with LC-MS/MS. Parameters of DHA and EPA were analyzed after baseline correction. A total of 37 subjects completed the study without any major violations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the co-administration of a single drug for the area under the concentration–time curve during the dosing interval at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.042 (0.971–1.118), 1.185 (1.113–1.262), 0.157 (0.091–0.271), and 0.557 (0.396–0.784), respectively. The GMRs (90% Cis) for the co-administration at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.150 (0.990–1.335), 1.301 (1.2707–1.1401), 0.320 (0.243–0.422), and 0.589 (0.487–0.712), respectively. The 90% CIs for most primary endpoints were outside the range of typical bioequivalence, indicating a pharmacokinetic interaction between atorvastatin and omega-3. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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17 pages, 5299 KiB

Open AccessArticle

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

by Liping Dong, Wenjuan Liu, Xiaoyuan Zhao, Feng Yu, Yungen Xu and Mengxiang Su

Pharmaceuticals 2022, 15(7), 801; https://doi.org/10.3390/ph15070801 - 27 Jun 2022

Cited by 3 | Viewed by 2415

Abstract

Limonin is one of the research hotspots in natural drug development. However, its low solubility in water leads to poor oral bioavailability, discouraging the further study of its potential as a candidate compound. In order to overcome this limitation, and to enhance its [...] Read more.

Limonin is one of the research hotspots in natural drug development. However, its low solubility in water leads to poor oral bioavailability, discouraging the further study of its potential as a candidate compound. In order to overcome this limitation, and to enhance its biological activities, a novel limonin derivative—HY-071085—was synthesized by structural modification, and has exhibited strong anti-inflammatory and analgesic activity. In order to achieve a thorough understanding of the biological actions of HY-071085 in vivo, this study evaluated the pharmacokinetics and bioavailability of HY-071085 in rats and beagle dogs, and the distribution and excretion in rats. Using ultra-high-performance liquid chromatography-tandem mass spectrometry, the kinetic profiles of HY-071085 in the plasma of healthy rats and beagle dogs after a single gavage, repeated gavages and the intravenous injection of HY-071085 were studied. The tissue distribution (heart, liver, spleen, lung, kidney, gastric tissue, intestine, brain, skin, testis, ovary and womb) and excretion of HY-071085 were also studied. These results showed that HY-071085 has nonlinear dynamic characteristics in rat and beagle dog plasma. It was found that the plasma concentrations of HY-071085 in female rats were significantly higher than those in male rats after a single oral administration. There were gender differences in the kinetic behavior of HY-071085 in rats; however, there was no difference identified in dogs. HY-071085 was mainly eliminated as metabolites in rats, and was distributed in most of the tissues except the brain, with the highest content being in the gastric tissue and intestinal arease, followed by the liver, spleen, fat, lung, kidney, ovary and heart. The bioavailability of HY-071085 in male and female rats was 2.8% and 10.8%, respectively, and was about 13.1% in beagle dogs. The plasma protein binding rate of HY-071085 in rats, beagle dogs and humans ranged from 32.9% to 100%, with obvious species differences. In conclusion, our study provides useful information regarding the absorption, distribution and excretion of HY-071085, which will provide a good base for the study of the mechanism of its biological effects. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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16 pages, 4141 KiB

Open AccessArticle

Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans

by Min-Soo Kim, Nora Lee, Areum Lee, Yoon-Jee Chae, Suk-Jae Chung and Kyeong-Ryoon Lee

Pharmaceuticals 2022, 15(6), 709; https://doi.org/10.3390/ph15060709 - 3 Jun 2022

Cited by 4 | Viewed by 3062

Abstract

Fexuprazan is a potassium-competitive acid blocker (P-CAB). The compounds in this newly developed drug family suppress intragastric acidity. As there are already other acid-suppressing drugs on the market, such as H₂ antagonists and proton pump inhibitors (PPIs), it would be informative to [...] Read more.

Fexuprazan is a potassium-competitive acid blocker (P-CAB). The compounds in this newly developed drug family suppress intragastric acidity. As there are already other acid-suppressing drugs on the market, such as H₂ antagonists and proton pump inhibitors (PPIs), it would be informative to compare the biological effects of fexuprazan against another approved drug with the same indication. The drug concentration predicted by the pharmacokinetic (PK) model could serve as an input function for a pharmacodynamic (PD) model. The apparent pharmacokinetics of fexuprazan could be described by a simpler model. However, a physiologically based pharmacokinetic (PBPK) model was developed in a previous study. A one-compartment model was also proposed in the present study. Both the newly suggested model and the previously validated PBPK model were used as input functions of the PD models. Our simulation revealed that the effects of fexuprazan could be effectively simulated by the proposed PK–PD models. A PK–PD model was also proposed for the oral administration of the PPI reference drug esomeprazole. A model-based analysis was then performed for intragastric pH using several dosing methods. The expected pH could be predicted for both drugs under several dosing regimens using the proposed PK–PD models. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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Review

Jump to: Research, Other

26 pages, 3586 KiB

Open AccessReview

Assessing Clinical Potential of Old Antibiotics against Severe Infections by Multi-Drug-Resistant Gram-Negative Bacteria Using In Silico Modelling

by Paschalis Paranos, Sophia Vourli, Spyros Pournaras and Joseph Meletiadis

Pharmaceuticals 2022, 15(12), 1501; https://doi.org/10.3390/ph15121501 - 30 Nov 2022

Cited by 8 | Viewed by 2728

Abstract

In the light of increasing antimicrobial resistance among gram-negative bacteria and the lack of new more potent antimicrobial agents, new strategies have been explored. Old antibiotics, such as colistin, temocillin, fosfomycin, mecillinam, nitrofurantoin, minocycline, and chloramphenicol, have attracted the attention since they often [...] Read more.

In the light of increasing antimicrobial resistance among gram-negative bacteria and the lack of new more potent antimicrobial agents, new strategies have been explored. Old antibiotics, such as colistin, temocillin, fosfomycin, mecillinam, nitrofurantoin, minocycline, and chloramphenicol, have attracted the attention since they often exhibit in vitro activity against multi-drug-resistant (MDR) gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The current review provides a summary of the in vitro activity, pharmacokinetics and PK/PD characteristics of old antibiotics. In silico modelling was then performed using Monte Carlo simulation in order to combine all preclinical data with human pharmacokinetics and determine the probability of target (1-log kill in thigh/lung infection animal models) attainment (PTA) of different dosing regimens. The potential of clinical efficacy of a drug against severe infections by MDR gram-negative bacteria was considered when PTA was >95% at the epidemiological cutoff values of corresponding species. In vitro potent activity against MDR gram-negative pathogens has been shown for colistin, polymyxin B, temocillin (against E. coli and K. pneumoniae), fosfomycin (against E. coli), mecillinam (against E. coli), minocycline (against E. coli, K. pneumoniae, A. baumannii), and chloramphenicol (against E. coli) with ECOFF or MIC₉₀ ≤ 16 mg/L. When preclinical PK/PD targets were combined with human pharmacokinetics, Monte Carlo analysis showed that among the old antibiotics analyzed, there is clinical potential for polymyxin B against E. coli, K. pneumoniae, and A. baumannii; for temocillin against K. pneumoniae and E. coli; for fosfomycin against E. coli and K. pneumoniae; and for mecillinam against E. coli. Clinical studies are needed to verify the potential of those antibiotics to effectively treat infections by multi-drug resistant gram-negative bacteria. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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Other

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11 pages, 966 KiB

Open AccessSystematic Review

Effectiveness of Pharmacokinetic-Guided Hydroxyurea Dose Individualization in Patients with Sickle Cell Anemia: A Mini-Review

by Joelma Santana dos Santos Neres, Sètondji Cocou Modeste Alexandre Yahouédéhou and Marilda Souza Goncalves

Pharmaceuticals 2023, 16(6), 857; https://doi.org/10.3390/ph16060857 - 8 Jun 2023

Cited by 2 | Viewed by 1666

Abstract

Inconsistent therapeutic responses have been observed among patients with sickle cell anemia (SCA) undergoing hydroxyurea (HU) following the adoption of the standardized protocol. Moreover, this treatment regimen necessitates a prolonged period to reach the maximum tolerated dose in which beneficial therapeutic effects are [...] Read more.

Inconsistent therapeutic responses have been observed among patients with sickle cell anemia (SCA) undergoing hydroxyurea (HU) following the adoption of the standardized protocol. Moreover, this treatment regimen necessitates a prolonged period to reach the maximum tolerated dose in which beneficial therapeutic effects are observed in most SCA patients. To overcome this limitation, several studies have performed HU dose adjustments in SCA patients based on individualized pharmacokinetic profiles. The present systematic mini-review aims to select and analyze published data to present an overview of HU pharmacokinetics studies performed in SCA patients, as well as evaluate the effectiveness of the dose adjustment strategy. A systematic search was performed in the Embase, Pubmed, Scopus, Web of Science, Scielo, Google Scholar, and the Virtual Library of Health databases from December 2020 to August 2022, with a total of five studies included. Inclusion criteria consisted of studies in which the dose adjustment was performed in SCA patients based on pharmacokinetic parameters. Quality analyzes were performed using QAT, while data synthesis was performed according to the Cochrane Manual of Systematic Reviews of Interventions. Analysis of the selected studies revealed improved HU treatment effectiveness using personalized dosages in SCA patients. Moreover, several laboratory parameters were utilized as biomarkers of the HU response, and methods designed to simplify the adoption of this practice were presented. Despite the scarcity of studies on this topic, HU-personalized treatment based on individualized pharmacokinetic profiles represents a viable alternative for SCA patients who are candidates for HU therapy, especially for pediatric patients. Registration number: PROSPERO CRD42022344512. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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