Roger K. Verbeeck

Pharmacokinetics and dosage adjustment in patients with renal dysfunction

IntroductionChronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment.MethodsInappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patients glomerular filtration rate (GFR) estimated by the Cockroft–Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required.DiscussionAccording to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drugs pharmacokinetics and pharmacodynamics.ConclusionIn conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.

Clinical Pharmacokinetics of Non-steroidal Anti-inflammatory Drugs

SummaryThe number of non-steroidal anti-inflammatory drugs (NSAIDs) available for clinical use has dramatically increased during the last decade. As a general rule, NSAIDs are well absorbed from the gastrointestinal tract, with the exception of aspirin (and possibly diclofenac, tolfenamic acid and fenbufen) which undergoes presystemic hydrolysis to form salicylic acid. Concomitant administration of NSAIDs with food or antacids may in some cases lead to delayed or even reduced absorption. The NSAIDs are highly bound to plasma proteins (mainly albumin), which limits their body distribution to the extracellular spaces. Apparent volumes of distribution of NSAIDs are, therefore, very low and usually less than 0.2 L/kg. The elimination of these drugs depends largely on hepatic biotransformation; renal excretion of unchanged drug is usually small (< 5% of the dose). Total body clearance is low and for most NSAIDs is less than 200 ml/min.The effect of age and disease on the disposition of NSAIDs has not been extensively studied. Due to the central role of the liver in the overall elimination of the majority of these compounds, hepatic disease will most likely lead to a significant alteration in their pharmacokinetic behaviour.NSAIDs have been reported to be involved in numerous pharmacokinetic drug interactions. Aspirin decreases the plasma concentrations of many other NSAIDs, although the clinical significance of this is uncertain. Due to the extremely high plasma protein binding of NSAIDs (around 99% in many cases), competition for the same binding sites on plasma proteins may be at least partly responsible for some interactions of NSAIDs with other highly bound drugs; however, another mechanism such as decreased metabolism or decreased urinary elimination is usually involved as well. The most important interactions with NSAIDs are those involving the oral anticoagulants and oral hypoglycaemic agents, though not all NSAIDs have been found to interact with these drugs.In clinical practice, there appear to be no clear-cut guidelines to assist the clinician in the selection of the most appropriate drug for an individual patient. The selection of an anti-inflammatory drug should be based on clinical experience, patient convenience (e.g. once or twice daily dosage schedule), side effects and cost. Since a marked interindividual variability exists in the clinical response to a given NSAID, clinicians prescribing these agents may try several of them sequentially until an adequate response is obtained.

Plasma Protein Binding of Drugs in the Elderly

SummaryBinding to plasma proteins can affect the pharmacokinetics and pharmacodynamics of drugs. Age is one of many factors which can affect plasma protein binding of drugs.Unfortunately, very few generalities can be drawn from the studies of the effect of age on protein binding. Whether age has an effect on protein binding is dependent not only on the drug, but also on the manner in which the study is conducted. Several studies involve patients with various disease states making assessment of the effect of age alone on protein binding difficult. Results of different studies on the same drug do not always agree — in one case finding no change in protein binding with age and in another, a significant increase or decrease in protein binding. Most drugs which exhibit increased binding (decreased free fraction) in elderly subjects are basic and tend to have a greater affinity for α1-acid glycoprotein than for albumin. The list of drugs exhibiting decreased binding (increased free fraction) in the elderly is longer and includes both acidic and basic drugs.The impact of changes in protein binding with age is dependent on the magnitude of the change, on the pharmacokinetic characteristics of the drug and on its therapeutic index. Some changes, although statistically significant, are not likely to be of importance clinically. From the studies reviewed, the free fraction is changed by greater than 50% in the elderly for only a few drugs, e.g. acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate and zimeldine.

Effect of age and sex on the plasma binding of acidic and basic drugs

SummaryProtein binding of chlorpromazine, propranolol, meperidine, desipramine, salicylic acid and phenytoin was determined in plasma of 64 healthy volunteers (35 males and 29 females). An attempt was made to identify factors affecting the plasma protein binding of these drugs. Whereas plasma albumin levels decreased as a function of age in both sexes, α1-acid glycoprotein levels increased with age, but the increase was more pronounced in males. The free plasma fraction of the acidic drugs (salicylic acid, phenytoin) and despiramine (a base) showed a significant (p<0.005) negative correlation with plasma albumin levels. The free fractions of the other three basic drugs (chlorpromazine, propranolol, meperidine) in plasma showed a significant (p<0.005) negative correlation with α1-acid glycoprotein plasma levels. Plasma protein binding of salicylic acid, phenytoin and desipramine decreased as a function of age. Plasma protein binding of chlorpromazine, propranolol and meperidine was virtually unaffected by age or was slightly increased (chlorpromazine). Only in the case of salicylic acid could a statistically significant difference be demonstrated between males and females in the free fraction-age relationship. Stepwise multiple linear regression analysis, including age and blood chemistry values such as hematocrit, bilirubin, cholesterol, triglycerides, creatinine, BUN, albumin and α1-acid glycoprotein as independent variables, identified age as the variable explaining most of the variability in plasma binding of salicylic acid, phenytoin and desipramine. For chlorpromazine, propranolol and meperidine α1-acid glycoprotein was the most important determinant of plasma protein binding.

Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients.

Tacrolimus is a potent immunosuppressive agent used to prevent allograft rejection. The pharmacokinetics of tacrolimus have been studied in healthy volunteers and transplant recipients, mostly by using immunoassays to measure tacrolimus in plasma or blood. However, because of the cross-reactivity for certain tacrolimus metabolites of the antibodies used, these methods often lack specificity. This should be carefully taken into account when interpreting pharmacokinetic results for tacrolimus.In adult patients, tacrolimus is generally rapidly absorbed following oral administration (the time to reach maximum concentration is 1 to 2 hours), but in some patients absorption is slow or even delayed. Because of presystemic elimination, the oral bioavailability is low (around 20%) but may vary between 4 and 89%. Tacrolimus is highly bound to erythrocytes. Its binding to plasma proteins varies between 72 and 98% depending on the methodology used. Because of the extensive partitioning of tacrolimus into erythrocytes, its apparent volume of distribution (Vd) based on blood concentrations is much lower (1.0 to 1.5 L/kg) compared with values based on plasma concentrations (about 30 L/kg). Tacrolimus is metabolised by cytochrome P450 (CYP) 3A4 to at least 10 metabolites, some of which retain significant activity. Biliary excretion is the route of elimination of the tacrolimus metabolites. Systemic plasma clearance of tacrolimus is very high (0.6 to 5.4 L/h/kg), whereas blood clearance is much lower (0.03 to 0.09 L/h/kg). The terminal elimination half-life (t1/2β) of tacrolimus is approximately 12 hours (with a range of 3.5 to 40.5 hours).Only limited information is available on the pharmacokinetics of tacrolimus in paediatric patients. The rate and extent of tacrolimus absorption after oral administration do not seem to be altered in paediatric patients. The Vd of tacrolimus based on blood concentrations in paediatric patients (2.6 L/kg) is approximately twice the adult value. Blood clearance of tacrolimus is also approximately twice as high in paediatric (0.14 L/h/kg) compared with adult (0.06 L/h/kg) patients. Consequently, t1/2β does not appear modified in children, but oral doses need to be generally 2-fold higher than corresponding adult doses to reach similar tacrolimus blood concentrations. More pharmacokinetic studies in paediatric patients are, however, needed to rationalise the use of therapeutic drug monitoring for optimisation of tacrolimus therapy in this patient population.

Effects of age and sex on piroxicam disposition

Piroxicam kinetics were studied after a single, oral, 20‐mg capsule was taken by 12 young (six women, six men) and 13 elderly (seven women, six men) healthy subjects. Plasma samples were drawn for 216 hr after dosing. Plasma protein binding was studied in vitro by equilibrium dialysis and piroxicam concentrations were measured by HPLC with ultraviolet detection. The apparent volume of distribution was smaller in elderly women (7.8 ± 0.4 l) than in young men (11.3 ± 0.3 l) and elderly men (10.8 ± 0.8 l). There were no such differences when the apparent volume of distribution was normalized for total body weight. There was a strong correlation between total body weight and apparent volume of distribution in all subjects (r = 0.83). Plasma protein binding of piroxicam ranged from 98.90% to 99.54% bound and was not affected by age or sex. Piroxicam body clearance in elderly women (0.026 ± 0.002 ml/min/kg) was approximately 33% lower than in young women (0.039 ± 0.003 ml/min/kg). This difference was reflected in different t½s of 61.7 and 44.9 hr. Predicted steady‐state plasma piroxicam concentrations were 5.7 µg/ml in young women, 5.4 µg/ml in young men, 5.7 µg/ml in elderly men, and 9.3 µg/ml in elderly women. The high value in elderly women results from the lower piroxicam body clearance and total body weight. Our data suggest that healthy elderly women eliminate piroxicam at a slower rate than healthy young women. The clinical significance of these data needs to be assessed in patients.

Pharmacokinetic drug interactions with nonsteroidal anti-inflammatory drugs.

SummaryNonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Drug interactions with this class of compounds are frequently reported and can be pharmacokinetic and/or pharmacodynamic in nature. The pharmacokinetic interactions can be divided into 3 classes: (1) drugs affecting the pharmacokinetics of an NSAID, (2) an NSAID interfering with the pharmacokinetics of another NSAID and (3) NSAIDs altering the pharmacokinetics of another drug.Although the pharmacokinetics of some NSAIDs may be significantly affected by the concurrent administration of certain other drugs (including other NSAIDs), this type of interaction only occasionally leads to serious complications. Concurrent administration of antacids or sucralfate may delay the rate of oral absorption of NSAIDs but generally has little effect on the extent. Use of antacids increases urinary pH, leading to increased renal excretion of unchanged salicylic acid and decreased plasma concentrations of this antirheumatic agent. The H2-receptor blocking agent cimetidine inhibits the oxidative metabolism of many concurrently administered drugs, including certain NSAIDs. Probenecid inhibits the renal secretion of drug glucuronides and this will lead to accumulation in plasma of those NSAIDs eliminated primarily by the formation of labile acyl glucuronides such as naproxen, ketoprofen, indomethacin, carprofen. Cholestyramine decreases the oral absorption of many concurrently administered drugs, including NSAIDs. It may also decrease plasma concentrations of those NSAIDs undergoing enterohepatic circulation (e.g. piroxicam, tenoxicam) by interrupting the enterohepatic cycle. Corticosteroids stimulate the clearance of salicylic acid, leading to low plasma salicylate concentrations. Plasma concentrations of many NSAIDs are significantly reduced when the NSAID is coadministered with aspirin. The clinical relevance of most of these interactions is not well established. However, in those cases where the interaction results in elevated plasma concentrations of the NSAID, special caution should be exercised to avoid excessive accumulation of the NSAID especially in elderly and/or very sick patients who may be more sensitive to the more serious gastroduodenal and renal side-effects of these agents.By virtue of their pharmacokinetic and pharmacodynamic properties, NSAIDs may significantly affect the disposition kinetics of a number of other drugs. They can displace other drugs from their plasma protein binding sites, inhibit their metabolism or interfere with their renal excretion. If the affected drug has a narrow therapeutic index, the interaction may be clinically significant. The pyrazole NSAIDs (phenylbutazone, oxyphen-butazone, azapropazone) inhibit the metabolism of many drugs such as the coumarin anticoagulants, oral antidiabetics and anticonvulsants such as phenytoin. Salicylates displace oral anticoagulants from their plasma protein binding sites. In addition, aspirin increases the risk of bleeding by inhibition of platelet function and by production of gastric erosions. The hypoglycaemic effect of sulfonylureas may be enhanced by large doses of salicylates through an intrinsic hypoglycaemic effect. In all these cases, alternative NSAIDs which do not interact with these agents should be used. Most, if not all, NSAIDs interfere with the renal excretion of lithium and methotrexate, which could lead to severe toxic reactions due to elevated plasma concentrations of these 2 drugs.Finally, clinically important interactions occur between NSAIDs and diuretics and antihypertensive agents. These interactions are largely pharmacodynamic in nature and in most cases seem to be the result of the prostaglandin inhibitory effects of the NSAIDs.

Extrahepatic glucuronidation of propofol in man: possible contribution of gut wall and kidney

Abstract.Objective: Results from clinical pharmacokinetic studies of propofol indicate that this i.v. anaesthetic agent may undergo significant extrahepatic glucuronidation. We have investigated whether glucuronidation of propofol takes place in the kidney and/or the gut wall. First, propofol concentrations were measured in arterial (radial artery) and portal venous blood of 12 cirrhotic patients with trans internal jugular porto-systemic shunting (TIPSS).Results: In 7 of the 12 patients arterial propofol concentrations were higher than portal venous concentrations. In the remaining patients, propofol concentrations were higher in the portal vein than the radial artery. Since an additional study in 5 patients anaesthetized with propofol while undergoing cholecystectomy showed propofol and an acid-labile conjugate of it in bile, it is difficult to interpret the results in patients with TIPSS due to the possibility of enterohepatic cycling. Next, in vitro studies with human liver (n = 5), kidney (n = 5) and small intestinal (n = 5) microsomes showed that all three tissues were capable of forming propofol glucuronide. Vmax for propofol glucuronidation was approximately 3 to 3.5 times higher in kidney (5.56 nmol ⋅ min−1⋅ mg−1 protein) than liver (1.80 nmol ⋅ min−1⋅ mg−1 protein) and small intestine (1.61 nmol ⋅ min−1⋅ mg−1 protein).Conclusion:Based on these in vitro results, it is concluded that extrahepatic glucuronidation in the small intestine and especially in the kidney may contribute to the overall glucuronidation of propofol in man.

Blood microdialysis in pharmacokinetic and drug metabolism studies.

Microdialysis is a sampling technique allowing measurement of endogenous and exogenous substances in the extracellular fluid surrounding the probe. In vivo microdialysis sampling offers several advantages over conventional methods of studying the pharmacokinetics and metabolism of xenobiotics, both in experimental animals and humans. In the first part of this review article various practical aspects related to blood microdialysis will be discussed, such as: probe design, surgical implantation techniques, methods to determine the in vivo relative recovery of the analyte of interest by the probe, special analytical considerations related to small volume microdialysate samples, and pharmacokinetic calculations based on microdialysis data. In the second part of this review a few selected applications of in vivo microdialysis sampling to investigate pharmacokinetic processes are briefly discussed: determination of in vivo plasma protein binding in small laboratory animals, distribution of drugs across the blood-brain barrier, the use of microdialysis sampling to study biliary excretion and enterohepatic cycling, blood microdialysis sampling in man and in the mouse, and in vivo drug metabolism studies.

Intravenous Microdialysis in the Mouse and the Rat: Development and Pharmacokinetic Application of a New Probe

AbstractPurpose. A flexible microdialysis probe was designed for intravenous sampling in small laboratory animals. Methods. Surgical techniques were developed to implant this probe via the femoral vein in the vena cava of the mouse and the rat. The in- and outlet of the probe were exteriorized above the tail of the animal and were directly connected to the microsyringe pump for perfusate delivery and to the injection valve for on-line HPLC analysis of the microdialysate samples. Results. The in vitro recoveries of flurbiprofen and naproxen for these probes were 68.2 ± 6.9% (mean ± S.D., n= 12) and 66.5 ± 7.3%, respectively. The relative loss by in vivo retrodialysis, measured the day after the implantation of the probes, was 66.1 ± 8.8% for flurbiprofen and 60.9 ± 9.9% for naproxen. The pharmacokinetics of unbound flurbiprofen were studied following i.v. bolus administration of flurbiprofen to the mouse (n = 4) and the rat (n = 6) with on-line HPLC analysis of microdialysates every 10 minutes during 6 to 8 hours. Flurbiprofen microdialysate concentrations were converted to unbound concentrations using the in vivo loss of flurbiprofen by retrodialysis carried out just before the start of the pharmacokinetic experiment. The integrity of the probe throughout the experiment was monitored by continuous retrodialysis of naproxen. Conclusions. The developed techniques can be used to carry out routine pharmacokinetic studies in the mouse and the rat as illustrated by our experiments with flurbiprofen, a compound with very high plasma protein binding.