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Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase–positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5′-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. Thirty-two patients received a single oral dose of a probe drug on Day − 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration–time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. ClinicalTrials.gov: NCT01970865.

Lower respiratory tract infections are common in adult patients with cystic fibrosis (CF) and are frequently caused by Pseudomonas aeruginosa, resulting in chronic lung inflammation and fibrosis. The progression of multidrug-resistant strains of P. aeruginosa and alterations in the pharmacokinetics of many antibiotics in CF make optimal antimicrobial therapy a challenge, as reflected by high between- and inter-individual variability (IIV). This review provides a synthesis of population pharmacokinetic models for various antibiotics prescribed in adult CF patients, and aims at identifying the most reported structural models, covariates and sources of variability influencing the dose–concentration relationship. A literature search was conducted using the PubMed database, from inception to August 2020, and articles were retained if they met the inclusion/exclusion criteria. A total of 19 articles were included in this review. One-, two- and three-compartment models were reported to best describe the pharmacokinetics of various antibiotics. The most common covariates were lean body mass and creatinine clearance. After covariate inclusion, the IIV (range) in total body clearance was 27.2% (10.40–59.7%) and 25.9% (18.0–33.9%) for β-lactams and aminoglycosides, respectively. IIV in total body clearance was estimated at 36.3% for linezolid and 22.4% for telavancin. The IIV (range) in volume of distribution was 29.4% (8.8–45.9%) and 15.2 (11.6–18.0%) for β-lactams and aminoglycosides, respectively, and 26.9% for telavancin. The median (range) of residual variability for all studies, using a combined (proportional and additive) model, was 12.7% (0.384–30.80%) and 0.126 mg/L (0.007–1.88 mg/L), respectively. This is the first review that highlights key aspects of different population pharmacokinetic models of antibiotics prescribed in adult CF patients, effectively proposing relevant information for clinicians and researchers to optimize antibiotic therapy in CF.

Pharmacological treatment of patients with Alzheimer’s disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory. Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a minor route of elimination for this drug. Pharmacokinetic data pertaining to eptastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period. Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum. Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver, and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites inthe cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier. Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment. Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has linear pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion. To achieve adequate drug concentrations in the brain, different methods have been devised, both invasive (implantable drug infusion pumps and polymer drug-delivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can protect the drug from degradation, etc.) methods. These methods may provide more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being assessed in clinical trials.

Malnutrition is usually complex, many deficiencies occurring simultaneously. Changes occur in almost every organ of the body. Apart from the pathophysiological changes which occur in protein-calorie malnutrition, vitamin, mineral and trace element deficiency is accompanied by diverse metabolic changes in tissues. As a consequence there is large potential for alteration of drug response in malnutrition, not only because of possible changes in drug kinetics but also because of changes in tissue uptake and localisation of drugs and potential alteration in drug-receptor interactions. The risk of susceptibility to drug-induced damage may also be increased. The functional status of the gastrointestinal tract is markedly altered in malnourished individuals and as a consequence the rate and extent of drug absorption is likely to be altered. First pass metabolism (intestinal and hepatic) is also likely to be altered. The profile of plasma proteins is considerably changed in malnourished individuals. In most cases, there is hypoalbuminaemia, the degree varying with the severity of malnutrition. Globulins however, are elevated, particularly in cases of infection. Lipoproteins are also reduced in states of malnutrition but there is no information on α1-acid glycoproteins, which bind basic drugs. Malnutrition, by altering the total body water, body composition and drug binding can lead to changes in the volume of distribution of a drug, depending on its physicochemical properties and its ability to bind to macromolecules. Although electronmicroscopc studies indicate changes in endoplasmic reticulum, liver function in malnutrition seems to be generally well preserved. However, biotransformation of drugs may be altered due to changes in drug metabolising hepatic enzyme activity, alteration in drug binding characteristics of proteins and the significant metabolic and hormonal changes in malnutrition. There may be abnormalities in biliary excretion which may affect drug elimination, at least in severe forms of protein-calorie malnutrition. Severe malnutrition can lead to changes in cardiac and renal function. These changes may be indirectly responsible for alterations in excretion mechanisms. Malnutrition can lead to changes in renal function, although this may not be a uniform change and there are very little data on renal excretion mechanisms and their relationship to drug elimination in malnutrition. Cardiac function also seems to be affected in malnutrition, particularly in children. There is reduction in cardiac output and prolonged circulation time; changes which may indirectly be responsible for decreased renal and hepatic blood fiow. Animal studies reveal that a number of macro- and micronutrient deficiencies can result in alteration in the rate of drug metabolism. Deficiencies in proteins, dietary fat, minerals and vitamins have all been shown to influence the activity of the mixed function oxidases. However, nutritional-pharmacological interactions in human populations are not as simple as observed under experimental conditions where most of the procedures are standardised and the number of variables minimised. A wide variety of environmental factors and complex multiple nutritional deficiencies react and modify nutritional-pharmacological inter-relationships in a human population. There are very few systematic studies of drug kinetics and drug response in malnutrition states in human populations. There is some evidence that absorption of oral tetracycline might be defective, but intramuscular penicillin and streptomycin seem to be absorbed adequately. The volume of distribution of tetracycline is markedly reduced in undernourished individuals. Although plasma albumin binding of a number of drugs has been shown to be reduced in malnourished individuals, with drugs such as tetracycline, phenylbutazone and sulphadiazine there is an increased rate of elimination. This is most probably due to increased amounts of free drug being available for metabolism. Studies of drug biotransformation in malnourished individuals are also as yet inadequate, but there have been a few reports of decreased rates of metabolism with drugs such as chloroquine, tetrachlorethylene and chloramphenicol. Observations on antipyrine pharmacokinetics in protein calorie malnutrition, anaemia, mineral deficiency and on experimental manipulation of proteins and carbohydrates in the diet, indicate that mixed function oxidases can be altered. However, the clinical significance of such findings are yet to be evaluated. The role of nutritional factors in development of cancer has attracted considerable attention. Some studies suggest that nutrition, cancer and drug metabolism (rate of hydroxylation) may be closely interlinked. Evaluation of drug kinetics and drug response in malnutrition must be studied systematically with a range of drugs of different physicochemical and pharmacokinetic properties. The relationship of drug kinetics, particularly drug metabolism, in various deficiency disorders to other environmental factors should also be established.

We determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin. In vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients. All macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 ± 0.6 vs 0.9 ± 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05). Macrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug–drug interaction of enzalutamide and oxycodone. A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) method. Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC0–8 h and Cmax of oxycodone with, respectively, 44.7% (p < 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC0–8 h and Cmax of the active metabolite oxymorphone were 74.2% (p < 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC0–8 h and Cmax of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide. Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.