Unusual Pharmacokinetics Research Articles

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target-Mediated Drug Disposition Model.

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM-1h-1), and the first-order dissociation rate constant (estimated to be 0.11h-1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials.

A Massive Acetaminophen Overdose with Unusual Pharmacokinetics

A clinical case report demonstrates the importance of managing a massive overdose of immediate-release acetaminophen using the same approach reserved for an overdose involving an extended-release formulation because of altered pharmacokinetics. RésuméCet article présente un rapport de cas cliniques démontrant l’importance de traiter une surdose mas-sive d’acétaminophène à libération immédiate en utilisant la même approche que celle utilisée pour traiter une surdose mettant en cause une préparation à libération prolongée en raison de la modification de la pharmacocinétique.

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014-2022.

The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine’s capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.

Malfunctioning sufentanil intrathecal pain pump: a case report

BackgroundSufentanil is a potent opioid uncommonly used to manage pain and is rarely administered via an intrathecal pain pump system.Case presentationThis case illustrates the use of intrathecal sufentanil in a 50-year-old Caucasian man for the management of chronic pain; however, the intrathecal drug delivery system experienced a malfunction which led to 1/100th output of the correct dosage. Interesting aspects of this case report include the uncommon choice of sufentanil use for an intrathecal drug delivery system, as well as the unusual pharmacokinetics of this drug. Specifically, this patient did not experience the major withdrawal that would be expected given significant under dosing of opioid, and this may be explained by the lipophilicity and context-sensitive half-times of sufentanil.ConclusionsBecause of the absence of a clinically significant withdrawal in this case report, clinicians must be aware of relevant pharmacokinetic properties and unusual intrathecal drug delivery system technologies that influence a patient’s response when device malfunction occurs.

Therapeutic monitoring of amiodarone: pharmacokinetics and evaluation of the relationship between effect and dose/concentration

Amiodarone is the most effective agent in the therapy of arrhythmias. However, the clinical effect of acute and chronic treatment is unclear and there are differences irrespective of comparable plasma/myocardial amiodarone and its metabolite desethylamiodarone concentations as well. Its unusual pharmacokinetics results in interindividual variation in plasma levels. The association between amiodarone and desethylamiodarone plasma levels and clinical efficacy is difficult to evaluate. This review was carried out to assess whether there is any objective correlation between amiodarone and desethylamiodarone plasma levels and the clinical effect. We summarized the results of relevant studies and clarified the relationship between plasma levels and effect vis á vis the pharmacokinetics and pharmacogenetics of this drug. Certain correlation was seen with oral amiodarone therapy, in others, plasma amiodarone levels were unrelated to therapeutic response and showed no correlation with changes in electrocardiogram or electrophysiological parametres. Several studies show that plasma concentration ranging between 0.5 and 2.5 mg/L appears to be the most effective, others demonstrate no difference between responders and non-responders. One way of interpreting plasma levels is to establish an individual patient´s effective concentration. Therapeutic drug monitoring can contribute to determining optimal concentration.

Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock

Objective: Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment.Case details: A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX® vs 4.3 (www.lixoft.com). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035–0.5 μg/mL). Data best fitted a one compartmental model with Michaelis–Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h−1, Michaelis constant [Km], 1.97 mg L−1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h.Conclusion: The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.

A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to d-amfetamine, methylphenidate and modafinil

Lisdexamfetamine dimesylate, which consists of l-lysine covalently bound to d-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield d-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include d-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, d-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5–1.5 mg/kg [d-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its d-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0–10 mg/kg, p.o.) and d-amfetamine (0.1–1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal d-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as d-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and d-amfetamine by 3.4× and 2.2×, respectively. Modafinil (50–200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self-administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [d-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to d-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics.

Lisdexamfetamine and immediate release d-amfetamine – Differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity

Lisdexamfetamine mesylate (Vyvanse®) is a novel prodrug approved for attention deficit hyperactivity disorder (ADHD). It is metabolised to d-amfetamine and l-lysine. In drug-experienced humans, lisdexamfetamine evoked lower “Drug liking” scores on Drug Rating Questionnaire (DRQ) scales than immediate-release (IR) d-amfetamine. This study investigated why lisdexamfetamine may have lower abuse potential and a better therapeutic window than d-amfetamine.We compared the pharmacokinetic/pharmacodynamic relationships of lisdexamfetamine and IR d-amfetamine in freely-moving rats by measuring simultaneously extracellular concentrations of striatal dopamine, plasma concentrations of d-amfetamine and lisdexamfetamine, and locomotor activity.At equivalent doses (1.5 mg/kg d-amfetamine base), lisdexamfetamine produced smaller, but more sustained, increases in striatal dopamine efflux than d-amfetamine and substantially less locomotor activation. Consistent with it being a prodrug, increased striatal dopamine and locomotion correlated with plasma concentration of its metabolite, d-amfetamine, but not the parent compound. Compared with IR d-amfetamine, lisdexamfetamine produced an identical AUC for plasma d-amfetamine, but a 50% lower Cmax and significantly delayed tmax.Where a hysteresis relationship did exist between plasma concentrations of d-amfetamine and striatal dopamine or locomotor activity, they were anticlockwise in direction for lisdexamfetamine and IR d-amfetamine. For extracellular striatal dopamine (neurochemical mediator) and locomotor activity (functional outcome), it was anticlockwise for lisdexamfetamine, but clockwise for IR d-amfetamine. This shows that lisdexamfetamine produced less pronounced behavioural activation as dopamine concentrations increased, but activity was maintained for longer when they declined. These findings help explain why the unusual pharmacokinetics of lisdexamfetamine evoked lower “Drug liking” scores than IR d-amfetamine and also suggest therapeutic window between efficacy and stimulant side-effects will be larger.

Absorption and Disposition of Scutellarin in Rats: A Pharmacokinetic Explanation for the High Exposure of Its Isomeric Metabolite

Scutellarin or scutellarein-7-O-glucuronide (S-7-G) is a flavonoid used in the treatment of cardiovascular diseases. After oral administration to humans, S-7-G can hardly be detected, whereas its isomeric metabolite [scutellarein-6-O-glucuronide (S-6-G)] dominates in plasma. A preliminary study in rats also revealed a low bioavailability of S-7-G, as well as a high plasma concentration of S-6-G. Therefore, the present study tried to explore the possible causes of the unusual pharmacokinetics of scutellarin in humans through investigating the absorption and disposition of S-7-G in rats. After oral administration to rats, S-7-G was largely hydrolyzed in the intestinal tract and was absorbed as aglycone. While passing through the intestinal wall, aglycone was extensively glucuronidated into S-7-G and S-6-G (approximately 20:1), which subsequently entered the mesenteric blood (approximately 15:1). However, because S-7-G exhibited more rapid uptake in hepatocytes, was glucuronidated at a 2.7-fold higher rate in the liver, and was excreted in greater amounts through bile and urine than S-6-G, the S-7-G/S-6-G ratio eventually declined to approximately 1.5:1 in the systemic circulation. Findings revealed that S-7-G cannot be absorbed directly; S-7-G and S-6-G in the body were mostly generated from aglycone in the intestinal wall; a larger amount of S-7-G than S-6-G entered the mesenteric blood at the absorption stage, but the gap between them shrank quickly mainly because of the higher hepatic first-pass elimination of S-7-G. These findings in rats are of great value as reference for further study to accurately interpret the pharmacokinetics of S-7-G in humans.

A first-in-human phase I clinical trial of CXR1002 in patients (pts) with advanced cancer.

3063 Background: CXR1002, an ammonium salt of perfluorooctanoic acid, is a lipid mimetic that causes ER stress and inhibits PIM kinases. Aims of this study were to assess the tolerability, safety and pharmacokinetics (PK) and to identify the recommended phase II dose (RP2D) of CXR1002 administered orally once weekly. Methods: Sequential cohorts of pts with advanced refractory solid tumors were enrolled. Cohort 1 received a single dose of CXR1002 followed by once weekly dosing commenced 6 weeks (wks) later. Subsequent cohorts received CXR1002 once wkly. Dose escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. Plasma levels of CXR1002 were determined by LC-MS/MS at the following time-points: pre-dose, 2, 3, 4, 24 hours post-dose for the first 6 wks then 6 wkly. Exploratory PD analyses included: serum leptin; plasma lipids, glucose and insulin. Results: 41 pts have been enrolled (23M / 18F); median age 63 (range 36-75); PS < 2; colorectal (n=16); pancreatic (n=5); other (n=20). CXR1002 was administered at 10 dose levels [mg (pts entered/evaluable)]: 50 (4/3), 100 (3/3), 200 (3/3), 300 (4/3), 450 (3/3), 600 (8/6), 750 (3/3), 950 (4/3), 1000 (3/3), 1200 (6/6). Median duration of therapy was 6.5 wks (range 0-40). DLT (grade 5 renal failure / grade 4 transaminitis; possibly drug-related) occurred in 1 pt at the 600mg dose. Protocol-defined MTD was not reached and the RP2D of 1,000mg wkly was based on tolerability of common cumulative drug-related toxicities, primarily: fatigue, nausea, vomiting, and diarrhea. Cmax was reached 1.5 hours after administration of a single dose of CXR1002 and maintained at a constant level over a 6 wk sampling period. CXR1002 was cumulative with wkly dosing with increased exposure seen with increasing dose level and duration. Reductions in LDL-cholesterol consistent with a PD effect were observed. Stable disease >12 wks was observed in 8 pts including pts with anaplastic thyroid (40 wks), pancreatic (35 wks), and cervical cancer (34 wks). Conclusions: The RP2D of CXR1002 when administered orally once wkly is 1,000mg. An expansion phase at this dose level will investigate biomarkers of PIM kinase inhibition. CXR1002 exhibits unusual PK with an extremely long t1/2.

Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding

In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics. Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA. A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 μmol/L) and human serum albumin less strongly (K(D) = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination. GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.

Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

BackgroundPreventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results.MethodsThe probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed.ResultsRecrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission.ConclusionCurrent dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence.

P.7.a.009 Long-term effectiveness and safety of lisdexamfetamine dimesylate in children aged 6−12 with attention-deficit/hyperactivity disorder

Lisdexamfetamine dimesylate, which consists of l-lysine covalently bound to d-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield d-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include d-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, d-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5–1.5 mg/kg [d-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its d-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0–10 mg/kg, p.o.) and d-amfetamine (0.1–1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal d-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as d-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and d-amfetamine by 3.4× and 2.2×, respectively. Modafinil (50–200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self-administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [d-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to d-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics.

Phenytoin toxicity: an easily missed cause of cerebellar syndrome

We present a series of cases of phenytoin toxicity where the diagnosis was initially missed. These patients all suffered unnecessary morbidity or investigations. The side-effects and unusual pharmacokinetics of phenytoin are discussed, as well as the array of potential drug interactions. We remind clinicians that phenytoin toxicity can easily mimic a cerebellar lesion or alcohol intoxication, and suggest that in accordance with National Institute for Clinical Excellence (NICE) guidelines phenytoin should no longer be used as a first-line treatment for epilepsy.

Azalides from Azithromycin to New Azalide Derivatives

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Azalides from Azithromycin to New Azalide Derivatives

Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a- became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics. The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4''-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4''-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines. Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.

Methadone for Persistent Pain in the Older Patient

Methadone is a synthetic opioid analgesic developed almost 60 years ago in response to a shortage of supplies of traditional opioids caused by the Second World War. Until a few years ago, this agent saw relatively little use other than as a maintenance therapy in narcotic addicts. A lack of knowledge regarding the unusual pharmacokinetics and pharmacodynamics of the drug and their impact on its clinical use invited therapeutic misadventures, which manifested as delayed severe toxicity. With the discovery and dissemination of the pharmacokinetic and pharmacodynamic behaviors and nonopioid mechanisms of action of methadone over the past 10–15 years, support for the use of methadone as a first-line opioid analgesic has been slowly progressing. Risk factors for excessive methadone accumulation have been identified, as have several dosing methodologies that allow its safe use, even in the oldest individuals. Methadone is no longer a medication only to be used by specialists in pain clinics. However, it should be used only by clinicians who are experienced in the use and monitoring of opioids, especially when moderate or high doses are required. This review summarizes the information necessary to allow its safe and effective use in the elderly population.

Human physiologically based pharmacokinetic model for propofol

BackgroundPropofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol.MethodsPKQuest, a freely distributed software routine , was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion.ResultsThe PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model.ConclusionA PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed.

Metabolite–P450 Complex Formation by Methylenedioxyphenyl HIV Protease Inhibitors in Rat and Human Liver Microsomes

P450 complex formation and the unusual pharmacokinetics of methylenedioxyphenyl HIV protease inhibitors were examined by in vitro studies using human and rat liver microsomes and by in vivo oral dosing studies. In vitro spectral studies indicated that the formation of a P450 complex having absorbance maxima at 425 and 456 nm was time and concentration dependent; 27–60% of the total P450 was complexed in dexamethasone-induced rat liver microsomes after a 30-min incubation with 100 μM HIV protease inhibitors. Methoxy substitution on the phenyl ring of the methylenedioxyphenyl moiety increased formation of the P450 complex, whereas chlorine substitution markedly decreased the P450 complexation. Kinetic studies on the P450 complex formation indicated that both methoxy and chlorine substitution affected the maximum complex formation rate ( V max), while it had little effect on K m values (∼10 μM). This complexation in human liver microsomes was inhibited markedly by an anti-CYP3A1 antibody. Furthermore, the P450 complex formation resulted in a time-dependent loss of CYP3A-catalyzed marker activities (testosterone 2β/6β-hydroxylase) in both rat and human liver microsomes. Collectively, these results point to the involvement of CYP3A isoforms in P450 complexation by methylenedioxyphenyl HIV protease inhibitors. Additionally, after oral administration to rats, one of these HIV protease inhibitors (Compound I), which complexed P450 to the greatest extent, showed no elimination over a period of 500 min after administration of the highest dose. It is suggested that formation of a quasi-irreversible metabolite–CYP3A complex with methylenedioxyphenyl HIV protease inhibitors was responsible for the CYP3A-selective time-dependent loss of catalytic function and the unusual dose-dependent pharmacokinetics after oral administration.

Therapeutic drug monitoring in special populations

Therapeutic drug monitoring (TDM) is commonly used to maintain "therapeutic" drug concentrations. Even in compliant patients, with "average" drug kinetics, TDM is useful to identify the causes of unwanted or unexpected responses, prevent unnecessary diagnostic testing, improve clinical outcomes, and even save lives. TDM has greatest promise in certain special populations who are: (a) prone to under- or overrespond to usual dosing regimens, (b) least able to tolerate, recognize, or communicate drug effects, or who are (c) intentionally or accidentally misdosed. TDM is especially useful in patients at the extremes of age, in adolescents, and in patients who are either taking multiple drugs or expressing unusual pharmacokinetics as a result of physiological, environmental, or genetic causes. Less-well-appreciated uses of TDM include prevention of dangerous underdosing of patients, investigation of adverse drug reactions, and identification of serious medication errors, even for a number of drugs that are not traditionally monitored. TDM can be useful for some drugs in any patient and for most drugs in some special populations.