Advancement and Strategies for the Development of Peptide-Drug Conjugates: Pharmacokinetic Modulation, Role and Clinical Evidence Against Cancer Management

: Currently, many new treatment strategies are being used for the management of cancer. Among them, chemotherapy based on peptides has been of great interest due to the unique features of peptides. This review discusses the role of peptide and peptides analogues in the treatment of cancer, with special emphasis on their pharmacokinetic modulation and research progress. Low molecular weight, targeted drug delivery, enhanced permeability, etc., of the peptide-linked drug conjugates, lead to an increase in the effectiveness of cancer therapy. Various peptides have recently been developed as drugs and vaccines with an altered pharmacokinetic parameter which has subsequently been assessed in different phases of the clinical study. Peptides have made a great impact in the area of cancer therapy and diagnosis. Targeted chemotherapy and drug delivery techniques using peptides are emerging as excellent tools in minimizing problems with conventional chemotherapy. It can be concluded that new advances in using peptides to treat different types of cancer have been shown by different clinical studies indicating that peptides could be used as an ideal therapeutic method in treating cancer due to the novel advantages of peptides. The development of identifying and synthesizing novel peptides could provide a promising choice to patients with cancer.

Therapeutic Drug Monitoring of Vancomycin in Patients with Altered Pharmacokinetics: A Narrative Review on Pharmacokinetic Assessments

Introduction: Vancomycin is a glycopeptide antibiotic that is considered as the drug of choice against many Gram-positive bacterial infections, especially Methicillin-resistant Staphylococcus aureus (MRSA). Also, it is a hydrophilic drug with predominantly renal elimination. Given the vancomycin narrow therapeutic index, therapeutic drug monitoring (TDM) is essential to achieve an optimum clinical response and avoid vancomycin-induced adverse drug reactions including nephrotoxicity and ototoxicity. Although different studies are available on vancomycin pharmacokinetic assessment and vancomycin TDM, still there are controversies regarding the selection among different pharmacokinetic parameters including trough concentration (Cmin), the daily area under the curve to minimum inhibitory concentration (AUC24h/MIC) ratio, AUC of intervals (AUCτ), elimination constant (k), vancomycin clearance (ClV) and methods of their calculations for TDM purposes. Methods: In this review, different pharmacokinetic parameters for vancomycin TDM have been discussed in detail along with corresponding advantages and disadvantages, based on the literature review. Determination of vancomycin concentration at steady state (Css) during 24h continuous injection are mentioned. Also, vancomycin pharmacokinetic assessments are discussed in detail in patients with altered pharmacokinetic parameters including those with renal and/or hepatic failure, critically ill patients, patients with burn injuries, intravenous (IV) drug users, obese and morbidly obese patients, those with cancer, patients undergoing organ transplantation, and vancomycin administration during pregnancy and lactation. Results and Discussion: An individualized dosing regimen is required to guarantee the optimum therapeutic results and minimize severe adverse reactions such as acute kidney injury (AKI) in these special groups of patients with altered pharmacokinetic parameters. Also, according to the pharmacoeconomic data on vancomycin TDM, pharmacokinetic assessments would be cost-effective in the mentioned groups of patients with altered pharmacokinetics and associated with shorter hospitalization period, faster clinical stability status, and shorter courses of inpatient vancomycin administration.

CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions

Palbociclib, ribociclib, and abemaciclib belong to the third generation of cyclin-dependent kinases inhibitors (CDKis), an established therapeutic class for advanced and metastatic breast cancer. Interindividual variability in the therapeutic response of CDKis has been reported and some individuals may experience increased and unexpected toxicity. This narrative review aims at identifying the factors potentially concurring at this variability for driving the most appropriate and tailored use of CDKis in the clinic. Specifically, concomitant medications, pharmacogenetic profile, and pathophysiological conditions could influence absorption, distribution, metabolism, and elimination pharmacokinetics. A personalized therapeutic approach taking into consideration all factors potentially contributing to an altered pharmacokinetic/pharmacodynamic profile could better drive safe and effective clinical use.

Antibiotics and its altered pharmacokinetics in the pediatric population : An evidence-based review

A better understanding of altered pharmacokinetic variables in the pediatric population is important to improve both the safety and efficacy of drug therapy. Even though pediatric patients are now considered as a special population for drug therapy, it should not give us the wrong idea of considering them like mini-adults. The difference in their pharmacokinetics may be attributed to the radical anatomical and physiological changes that happen with age. Antimicrobials are one of the most prescribed therapeutic agents, and they are used in the treatment of numerous infections. Children are always susceptible to various infections, which often results in their exposure to a wide variety of antibiotics at such an early age. Recent studies showed higher rates of antibiotic prescribing in the pediatric population. The pediatric population requires more attention when prescribing antibiotics due to the increased probability of serious adverse effects, the time required for the complete development of the organs, and augmented drug resistance.

Effect of Pomelo Juice on the Pharmacokinetics of Simvastatin, CYP3A2 Activity and Mdr1a, Mdr1b and Slc21a5 Expressions in Rats

Background: Food-drug interaction can decrease drug effectiveness or increase risk of drug toxicity. Simvastatin is widely used for treatment of hypercholesterolemia and hypertriglyceridemia. Therefore, this study aimed to investigate the effects of pomelo juice on the pharmacokinetics of simvastatin, CYP3a2 activity and Mdr1a, Mdr1b and Slc21a5 expressions in rats. Methods: Rats were divided into 4 groups including (i) control, (ii) pomelo that received pomelo juice orally twice daily for 7 days, (iii) simvastatin that received simvastatin on day 8, and (iv) simvastatin + pomelo juice. Plasma concentrations of simvastatin and simvastatin acid were analyzed using LC-MS/MS. Hepatic CYP3a2 activity was evaluated using midazolam hydroxylation assay. The expressions of hepatic and intestinal Mdr1a, Mdr1b and Slc21a5 were measured using the real-time RT-PCR. Results: Oral administration of pomelo juice for 7 days altered pharmacokinetic profiles of simvastatin and its primary active metabolite, simvastatin acid, in rats. Real-time RT-PCR analysis revealed that pomelo juice significantly suppressed the expression of intestinal Mdr1a and Mdr1b and hepatic Slc21a5. Rat hepatic CYP3a2 catalytic activity was also inhibited following pomelo juice administration. Conclusion: The results of this study suggested that there was a risk of potential drug interaction associated with inhibition of drug transporters and CYP3A caused by pomelo juice.

Drug Dosing in Acute Kidney Injury

The prevalence of acute kidney injury (AKI) among hospitalized patients has increased sharply over the past 10 to 20 years. One complicating factor in this population is that many pharmacologic agents that are administered to these patients are handled, to some degree, by the kidneys. These medications may experience altered pharmacokinetic and pharmacodynamic profiles in patients with renal dysfunction, increasing the chances of drug misadventures. Historically, drug dosing in patients with AKI has been approached in the same manner as in patients with chronic renal insufficiency (CRI). The majority of dosing recommendations for AKI have been extrapolated from studies performed in patients with stable CRI. Renal drug clearance, composed of glomerular filtration, tubular secretion, and renal drug metabolism, is affected by renal dysfunction. It is clear that there is a reduction in renal clearance of drugs and toxins in both AKI and CRI. However, the type of renal dysfunction may affect other parameters of drug handling. Thus, dosing stratagems extrapolated from patients with CRI may result in subtherapeutic drug concentrations and ineffective treatment. Achieving a balance between under- and overdosing requires rigorous monitoring and individualized dosing. Key words: acute kidney injury, drug dosing, pharmacokinetics

Drug Dosing in Acute Kidney Injury

The prevalence of acute kidney injury (AKI) among hospitalized patients has increased sharply over the past 10 to 20 years. One complicating factor in this population is that many pharmacologic agents that are administered to these patients are handled, to some degree, by the kidneys. These medications may experience altered pharmacokinetic and pharmacodynamic profiles in patients with renal dysfunction, increasing the chances of drug misadventures. Historically, drug dosing in patients with AKI has been approached in the same manner as in patients with chronic renal insufficiency (CRI). The majority of dosing recommendations for AKI have been extrapolated from studies performed in patients with stable CRI. Renal drug clearance, composed of glomerular filtration, tubular secretion, and renal drug metabolism, is affected by renal dysfunction. It is clear that there is a reduction in renal clearance of drugs and toxins in both AKI and CRI. However, the type of renal dysfunction may affect other parameters of drug handling. Thus, dosing stratagems extrapolated from patients with CRI may result in subtherapeutic drug concentrations and ineffective treatment. Achieving a balance between under- and overdosing requires rigorous monitoring and individualized dosing. Key words: acute kidney injury, drug dosing, pharmacokinetics

Palpitations and Asthenia Associated with Venlafaxine in a CYP2D6 Poor Metabolizer and CYP2C19 Intermediate Metabolizer

Cardiotoxicity has been extensively reported in venlafaxine (VEN) overdoses. Asthenia is also among the common side effects described for this antidepressant. VEN is metabolized mainly by CYP2D6 and to a minor extent by CYP2C19 to the major active metabolite O-desmethylvenlafaxine (ODV). Altered pharmacokinetic parameters in patients with polymorphisms in the CYP2D6 and CYP2C19 genes that result in decreased enzymatic activity have been documented. Here we describe a patient case of VEN associated palpitations and asthenia. The patient takes VEN extended release 150 mg twice daily. Genotyping confirmed the patient is a poor metabolizer for CYP2D6 and an intermediate metabolizer for CYP2C19. We propose that the palpitations and asthenia are related to sustained VEN exposure due to reduced metabolism.

Population pharmacokinetics and pharmacodynamics modeling to optimize dosage regimens of sulbactam in critically ill patients with severe sepsis caused byAcinetobacterbaumannii

Sulbactam is being considered as an alternative concomitant medication with other effective antibiotics for the treatment of multidrug-resistant (MDR)Acinetobacter baumanniiinfections. Pathophysiological changes in critically ill patients with severe sepsis, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors in determining therapeutic success. The aims of this study were (i) to examine the population PK parameters, and (ii) to assess the probability of target attainment (PTA) for sulbactam in patients with severe sepsis caused byA. baumannii. PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 4thday of drug administration in twenty-seven patients and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentration remained above the MIC (T>MIC) and 60%T>MIC. The central and peripheral volumes of distribution were 14.56 and 9.55 liters, respectively and total clearances of sulbactam were 2.26 liters/h and 7.64 liters/h in patients aged >65 years and ≤65 years, respectively. The high PTAs (≥90%) for targets of 40%T>MICand 60%T>MICwith a MIC of 4 μg/ml were observed when sulbactam was administered by a 4-h infusion of 1 g every 12 h and 1 g every 8 h, respectively. Sulbactam would be an alternative antibiotic option to coadminister with colistin for the treatment of infections caused by MDRA. baumannii. However, for pathogens with MICs of >4 μg/ml, higher dosage regimens of sulbactam are required.