Analysis of drug-impregnated paper samples seized in English prisons between 2018 and 2020.

Novel psychoactive substances (NPS) in the form of impregnated papers delivered to prisoners are of particular concern in prison settings, where they are commonly used by vaping. The purpose of this study was to create a qualitative method for identifying the various emerging NPS impregnated onto paper samples sent to prisoners. It helps to demonstrate that these findings can be used to predict drug prevalence and trends in prisons. Between 2018 and 2020, 1250 non-judicial paper samples seized from 12 English prisons were analysed to determine the NPSs being circulated. Approximately 1 cm2 paper were cut and added to 50 % (v/v) methanol in LCMS-grade water. Vortex-mixing was used to prepare extracts (30 min). Q-TOF LC/MS was used to screen the extracts. This study showed that synthetic cannabinoid receptor agonist (SCRA) was the most common drug group detected in impregnated paper seizures in English prisons between 2018 and 2020, followed by cocaine, heroin type drugs (A) and amphetamine, ketamine type drugs (B). Male prisons had a higher prevalence of SCRAs, whereas female prisons had a higher prevalence of A drugs. Furthermore, lower security prisons were found to have a higher prevalence of B drugs, pregabalin, gabapentin type drugs (C), and abused and prescription drugs than higher security prisons which unveiled a higher prevalence of nicotine. The findings of this study have revealed new information about drug use in prisons. This study will also aid in the identification of drug smuggling routes into jails, keeping prison staff up to date with the trends.

The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.

BACKGROUND: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS: For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS: NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.

Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults.

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

Analysis of illicit drugs in purchased and seized electronic cigarette liquids from the United Kingdom 2014-2021.

Increasing popularity and known shortfalls in the regulation of electronic cigarettes (ECs) emphasises the urgent need for closer content monitoring and for comprehensible information on their possible health effects. This study investigated components of EC liquids in samples submitted from 2014 to 2021 and discussed the trends driven by legislation changes. Samples originating from prisoners, teenagers and 'test purchases' of commercially available ECs were analysed by gas chromatography-mass spectrometry (GC-MS). For those containing delta-9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD), the content of these components was quantified by liquid chromatography with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) to show variation of these compounds in EC liquids; 112 EC liquids were included in this study. Nicotine was detected in 87 (78%) of the EC liquids analysed. Twenty-two, including samples from before and after introduction of the UK Psychoactive Substances Act (2016), contained one or more synthetic cannabinoid receptor agonist (SCRA). THC was detected in only 11 samples, whereas a single sample was found to contain CBD only. Six samples contained a mixture of THC and CBD. In all cases where information was available, the THC/CBD content was less than that stated on the product label. The data collected showed great variation in EC liquid content. Therefore, it is important that users are educated regarding risks associated with EC use. Additionally, substances now controlled under both the UK Misuse of Drugs Act and Psychoactive Substances Act were present. These substances each carry a potential risk to health, which is possibly exacerbated if multiple compounds are inhaled concomitantly.

In vitro metabolism of the new antifungal dapaconazole using liver microsomes.

Dapaconazole is a new antifungal imidazole that has been shown a high efficacy against several pathogenic fungi. This study aimed to investigate the interspecies variation in the in vitro metabolic profiles and in vivo hepatic clearance (CLH,in vivo) prediction of dapaconazole using liver microsomes from male Sprague Dawley rat, male Beagle dog and mixed gender human using a liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method. In addition, the produced metabolites were identified by ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS/MS). The microsomal protein concentration of 0.1 mg/mL and the incubation time of 10 min were employed for the kinetics determination, resulting in a sigmoidal kinetic profile for all species evaluated. The predicted CLH,in vivo was 6.5, 11.6 and 7.5 mL/min/kg for human, rat and dog, respectively. Furthermore, five metabolized products were identified. These findings provide preliminary information for understanding dapaconazole metabolism and the interspecies differences in catalytic behaviours, supporting the choice of a suitable laboratory animal for future pharmacokinetics and metabolism studies.

Limited sampling strategies for estimation of tacrolimus exposure in kidney transplant recipients receiving extended-release tacrolimus preparation.

Tacrolimus is the key component of most contemporary immunosuppressive drug regimens for the prevention of transplant rejection. Area under the concentration time curve over 24 h (AUC0-24 ) predicts efficacy, but predose (trough) tacrolimus blood concentration (C0 ) is currently used to guide dosing. In clinical or research situations where an estimate of AUC is required, collection of a full 24 h pharmacokinetic (PK) profile is cumbersome. Limited sampling strategies (LSSs) have been developed for some tacrolimus preparations but not for the new, extended-release, once-daily formulation of tacrolimus, ENVARSUS XR. Twenty-four kidney transplant recipients were enrolled in this study. Twenty-four tacrolimus PK profiles were obtained over 24 h. Multiple linear regression was used to generate LSSs with the best subset selection for accurate estimation of tacrolimus AUC0-24 . The predictive performance of each model was assessed in the evaluation group. The correlation between actual and predicted AUC0-24 was evaluated and mean percentage prediction error (MPE%), mean absolute percentage prediction error (MAE%), and root mean squared error (RMSE) were calculated for each prediction model to assess bias and precision. The selected LSSs were highly correlated to AUC0-24 compared with the correlation between C0 and AUC0-24 . Two and three sampling points limited sampling strategies: C0 , C2 , and C10 provide the most reliable and effective LSS for estimation of tacrolimus AUC0-24 in routine clinic use. These limited sampling models can be applied in therapeutic drug monitoring schemes to personalize tacrolimus dosing for kidney transplant recipients on treatment with extended-release tacrolimus.

Prospective Prediction of Dapaconazole Clinical Drug-Drug Interactions Using an In Vitro to In Vivo Extrapolation Equation and PBPK Modeling.

This study predicted dapaconazole clinical drug−drug interactions (DDIs) over the main Cytochrome P450 (CYP) isoenzymes using static (in vitro to in vivo extrapolation equation, IVIVE) and dynamic (PBPK model) approaches. The in vitro inhibition of main CYP450 isoenzymes by dapaconazole in a human liver microsome incubation medium was evaluated. A dapaconazole PBPK model (Simcyp version 20) in dogs was developed and qualified using observed data and was scaled up for humans. Static and dynamic models to predict DDIs following current FDA guidelines were applied. The in vitro dapaconazole inhibition was observed for all isoforms investigated, including CYP1A2 (IC50 of 3.68 µM), CYP2A6 (20.7 µM), 2C8 (104.1 µM), 2C9 (0.22 µM), 2C19 (0.05 µM), 2D6 (0.87 µM), and 3A4 (0.008−0.03 µM). The dynamic (PBPK) and static DDI mechanistic model-based analyses suggest that dapaconazole is a weak inhibitor (AUCR > 1.25 and <2) of CYP1A2 and CYP2C9, a moderate inhibitor (AUCR > 2 and <5) of CYP2C8 and CYP2D6, and a strong inhibitor (AUCR ≥ 5) of CYP2C19 and CYP3A, considering a clinical scenario. The results presented may be a useful guide for future in vivo and clinical dapaconazole studies.

Simultaneous quantification of cyclosporin, tacrolimus, sirolimus and everolimus in whole blood by UHPLC-MS/MS for therapeutic drug monitoring.

The aim of this study was to develop and validate a UHPLC-MS/MS assay to quantify cyclosporin (CYC), tacrolimus (TAC), sirolimus (SIR) and everolimus (EVE) in human whole blood for therapeutic drug monitoring. Analytes were extracted from 50 µL human whole blood by protein precipitation. The separation of the drugs was performed on an Acquity UPLC BEH C18 column. Analytes were eluted with a mobile phase consisting of 2 mM ammonium acetate with 0.1% formic acid (v/v) in deionised water and 2 mM ammonium acetate with 0.1% formic acid (v/v) in methanol at a flow rate of 300 µL/min in gradient elution. The method performance was evaluated by analysing patient blood samples and/or external quality control samples [proficiency testing (PT) scheme]. The method was linear from 23.75 to 1094.0, 1.3 to 42.4, 1.3 to 47.0 and 1.2-41.6 µg/mL for CYC, TAC, SIR and EVE, respectively. The within- and between-assay reproducibility results were ˂ 11%. Results from PT and patient sample quantification were comparable to those obtained previously by an in-house validated method using protein precipitation and liquid-liquid extraction. This method showed good analytical performance for quantifying CYC, TAC, SIR and EVE in whole blood over their respective calibration ranges.

Quantification of mycophenolic acid in human plasma by liquid chromatography with time-of-flight mass spectrometry for therapeutic drug monitoring.

This study presents, for the first time, the development and validation of a liquid chromatography and time-of-flight mass-spectrometry (LC-TOF-MS) based assay to quantify mycophenolic acid (MPA) in patient samples as part of a routine therapeutic drug monitoring service. MPA was extracted from 50 µl human plasma by protein precipitation, using sulindac as internal standard (IS). Separation was obtained on a Luna™ Omega polar C18 column kept at 40°C. The mobile phase consisted of a mixture of acetonitrile-deionized water (50:50, v/v) with 0.1% formic acid at a flow rate of 350 µl/min. Analyte and IS were monitored on a TOF-MS using a Jet-Stream™ (electrospray) interface running in positive mode. Assay performance was evaluated by analysing patient plasma (N = 69) and external quality assessment (N = 6) samples. The retention times were 2.66 and 2.18 min for MPA and IS, respectively. The lower limit of quantification of MPA was 0.1 µg/ml. The within- and between-assay reproducibility results ranged from 1.81 to 10.72%. Patient and external quality assessment sample results were comparable with those obtained previously by an in-house validated LC-MS/MS method. This method showed satisfactory analytical performance for the determination of MPA in plasma over the calibration range of 0.1-15.0 µg/ml.

Total body water is the preferred method to use in forensic blood-alcohol calculations rather than ethanol's volume of distribution.

During the prosecution and defence of drink-driving cases, forensic practitioners are often required to engage in various blood-alcohol calculations, such as whether or not the statutory limit was exceeded (e.g. 80mg/100mL, 0.08g/100mL or 0.80g/L). For this purpose, most forensic scientists utilize the Widmark equation, or some modification thereof, to calculate a person's blood alcohol concentration (BAC) based on information about the amount of ethanol consumed and the pattern of drinking. This equation comes in two main forms; one of which incorporates the apparent volume of distribution of ethanol (V) and the other a person's total body water (TBW). In this study, we utilised two independent data sets, one involving the determination of V for ethanol in 173 men and 63 women, and the other TBW determined for 582 men and 884 women. Those subjects included in the TBW group represented various racial groups (Caucasians, African Americans, Hispanics, Asians and Puerto Ricans), with body mass index (BMI) ranging from 17 to 80kg/m2. Both versions of the Widmark equation were evaluated in relation to their accuracy and precision in predicting TBW and/or V using the two most common anthropometric equations; those of Watson et al. and Forrest. Both anthropometric equations exhibited good accuracy (<4.3%) for the prediction of both TBW and V. However, the root mean square error was lower TBW was used for prediction (9.09-12.84%) rather than V (11.72-15.08%). Overall, this study has demonstrated (a) that blood-alcohol calculations are more reliable using TBW rather than V (b) that both equations (Watson et al. and Forrest) are applicable to ethnic groups other than Caucasians and (c) the Forrest equation predicts TBW in men and women with BMI from 17 to 35kg/m2 and that the Watson et al. equation works for those with more extreme BMI; females (17-80kg/m2) and males (17-67kg/m2).

ß-Lactam antimicrobial pharmacokinetics and target attainment in critically ill patients aged 1 day to 90 years: the ABDose study.

BACKGROUND: The pharmacokinetics of ß-lactam antibiotics in critical illness remain poorly characterized, particularly in neonates, children and the elderly. We undertook a pharmacokinetic study of commonly used ß-lactam antibiotics in critically ill patients of all ages. The aims were to produce a whole-life ß-lactam pharmacokinetic model and describe the extent to which standard doses achieve pharmacokinetic/pharmacodynamic targets associated with clinical cure. PATIENTS AND METHODS: A total of 212 critically ill participants with an age range from 1 day (gestational age 24 weeks) to 90 years were recruited from a UK hospital, providing 1339 pharmacokinetic samples. Population pharmacokinetic analysis was undertaken using non-linear mixed-effects modelling (NONMEM) for each drug. Pooled data were used to estimate maturation and decline of ß-lactam pharmacokinetics throughout life. RESULTS: Pharmacokinetic models for eight drugs were described, including what is thought to be the first benzylpenicillin model in critically ill adults. We estimate that 50% of adult ß-lactam clearance is achieved by 43 weeks post-menstrual age (chronological plus gestational age). Fifty percent of decline from peak adult clearance occurs by 71 years. Paediatric participants were significantly less likely than adults to achieve pharmacokinetic/pharmacodynamic targets with standard antibiotic doses (P < 0.01). CONCLUSIONS: We believe this to be the first prospective whole-life antibiotic pharmacokinetic study in the critically ill. The study provides further evidence that standard antibiotic doses fail to achieve pharmacokinetic/pharmacodynamic targets associated with clinical success in adults, children and neonates. Maturation and decline parameters estimated from this study could be adopted as a standard for future prospective studies.

A pragmatic pilot phase II randomised controlled trial of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) in adult patients who are undergoing heart surgery (PROPHESY).

BACKGROUND: Fresh frozen plasma (FFP) is the accepted standard treatment for clotting factor replacement in bleeding patients during or immediately after cardiac surgery. In the United Kingdom prothrombin complex concentrate (PCC) is not licensed in this setting, although it is being used in Europe because it has a higher concentration of clotting factor levels, and it can be administered rapidly and in small volume, resulting in less volume overload during cardiac surgery. METHODS: PROPHESY is a pragmatic, single-centre, open-label, randomised, controlled pilot trial that will assess whether it is feasible to perform a large trial in the future that will compare PCC versus FFP in patients who are bleeding (not on warfarin) and who require blood transfusion. Over a 15-month period, 50 patients will be randomised to PCC versus FFP if they develop active bleeding within 24 h of cardiac surgery and for whom the clinician has decided to administer FFP for treatment of bleeding. Standard laboratory and point-of-care assessments will be performed as per routine practice, and additional research blood samples will be taken at three time points to assess haemostasis. Subjects will be assessed daily up to hospital discharge or 30 days or death (whichever occurs first) and will be seen in follow-up for 90 days after surgery to assess for thromboembolic complications and hospital re-admission since discharge. Quality-of-life assessment will be performed pre-surgery and at 90 days post-surgery. We will also perform qualitative research with clinical experts and patients to explore the understanding of and experience with the interventions, as well as adherence to study procedures and protocol. DISCUSSION: There have been no randomised controlled trials that have compared the safety and efficacy of FFP versus PCC in cardiac surgery patients who are bleeding. This pilot study will assess if individual components of a large trial are deliverable to assess the safety and efficacy of the two blood products in the future. TRIAL REGISTRATION: EudraCT, 2018-003041-41; ClinicalTrials.gov, NCT03715348. Registered on 29 July 2018.

Variability in content and dissolution profiles of MDMA tablets collected in the UK between 2001 and 2018 - A potential risk to users?

3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) tablets are widely used recreationally, and not only vary in appearance, but also in MDMA content. Recently, the prevalence of high-content tablets is of concern to public health authorities. To compare UK data with other countries, we evaluated MDMA content of 412 tablets collected from the UK, 2001-2018, and investigated within-batch content variability for a sub-set of these samples. In addition, we investigated dissolution profiles of tablets using pharmaceutical industry-standard dissolution experiments on 247 tablets. All analyses were carried out using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data supported other studies, in that recent samples (2016-2018) tend to have higher MDMA content compared to earlier years. In 2018, the median MDMA content exceeded 100 mg free-base for the first time. Dramatic within-batch content variability (up to 136 mg difference) was also demonstrated. Statistical evaluation of dissolution profiles at 15-minutes allowed tablets to be categorized as fast-, intermediate-, or slow-releasing, but no tablet characteristics correlated with dissolution classification. Hence, there would be no way of users knowing a priori whether a tablet is more likely to be fast or slow-releasing. Further, within-batch variation in dissolution rate was observed. Rapid assessment of MDMA content alone provides important data for harm reduction, but does not account for variability in (a) the remainder of tablets in a batch, or (b) MDMA dissolution profiles. Clinical manifestations of MDMA toxicity, especially for high-content, slow-releasing tablets, may be delayed or prolonged, and there is a significant risk of users re-dosing if absorption is delayed.

Safety and Pharmacokinetics of Levobupivacaine Following Fascia Iliaca Compartment Block in Elderly Patients.

BACKGROUND: Fascia iliaca compartment block (FICB) is an increasingly popular analgesic technique in elderly patients with hip fracture. Despite requiring large volumes of local anaesthetic, there are no plasma pharmacokinetic data on FICB in elderly patients. OBJECTIVES: The objective of this study was to determine the pharmacokinetic profile of a levobupivacaine 75 mg (30 mL 0.25%) FICB dose in patients aged ≥ 80 years with fractured femur. METHODS: This was a single-arm descriptive pilot study. Twelve adults aged ≥ 80 years with hip fracture received FICB performed under ultrasound guidance. Venous blood was sampled at 10, 20, 30, 45, 60, 75, 90, 105, 120 and 240 min after injection. Total plasma levobupivacaine concentration was measured by mass spectrometry. The main outcome measures were pharmacokinetic parameters, including maximum observed plasma concentration (Cmax), time to reach Cmax (tmax) and area under the plasma concentration-time curve. RESULTS: The median (interquartile range [IQR]) Cmax was 0.82 µg/mL (0.47-1.03). tmax was 45 min (41:20-60:00). No evidence of toxicity was identified. Plasma levobupivacaine concentrations were below the threshold associated with toxicity in younger, healthy patients (2.6 µg/mL). No association was found between individual patient Cmax and α1-acid glycoprotein, weight or body mass index, although the study was not powered for these outcomes. CONCLUSIONS: Absorption of levobupivacaine was slow and all patients had plasma concentrations below the toxic threshold. This pharmacokinetic analysis concludes that the technique appears to be well-tolerated and efficacious at reducing pain and is associated with systemic plasma concentrations unlikely to be associated with major adverse effects in elderly patients. CLINICAL TRIAL REGISTRATION: ISRCTN27364035 (UK Clinical Trials Gateway).

Rapid Quantitation of Flecainide in Human Plasma for Therapeutic Drug Monitoring Using Liquid Chromatography and Time-of-Flight Mass Spectrometry.

BACKGROUND: Measurement of flecainide is useful to optimize dosage and minimize risks of toxicity. Furthermore, there is a need for urgent sample analysis when flecainide is used in transplacental therapy for fetal tachycardia. To this end, we have developed and validated a rapid assay for the measurement of flecainide in human plasma or serum, using a small sample volume (50 µL). METHODS: After a simple deproteination with zinc sulfate and methanol, prepared samples were injected onto a short (30 mm) analytical column and eluted using a rapid gradient elution. Detection was performed using time-of-flight mass spectrometry. Flecainide was quantified using flecainide-D4 as internal standard, with both compounds extracted from the total ion chromatogram using a ±5 ppm extraction window based on the theoretical m/z values for the protonated ions. RESULTS: The assay was linear over a putative therapeutic range (100-1500 mcg/L). Between- and within-assay imprecision and accuracy were <4.6% and 94.8%-110.0%, respectively. Matrix effects were minimal and were compensated for by flecainide-D4. There were no effects due to hemolysis or lipemia, and no carryover was apparent. Total analysis time was just 1.2 minutes (72 seconds). CONCLUSIONS: We have developed and validated a rapid method for the analysis of flecainide. The method is particularly suited for flecainide therapeutic drug monitoring, when analyzing samples from mothers receiving flecainide for the treatment of fetal tachycardia.

Amenamevir: Studies of Potential CYP3A-Mediated Pharmacokinetic Interactions With Midazolam, Cyclosporine, and Ritonavir in Healthy Volunteers.

Amenamevir (formerly ASP2151) is a helicase-primase inhibitor being developed for the treatment of herpesvirus infection. Amenamevir is both a substrate and inducer of cytochrome P450 (CYP) 3A4. Three studies were done in healthy volunteers to investigate potential CYP3A pharmacokinetic interactions with the following drugs: (1) Midazolam (probe substrate for CYP3A): After 10 days' pretreatment with amenamevir 400 mg daily, geometric mean maximum concentration of drug in blood plasma (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-∞ ) of midazolam 7.5 mg were about 68% and 51%, respectively, of those after midazolam alone. (2) Cyclosporine (substrate and inhibitor of CYP3A): After 5 days' pretreatment with cyclosporine 100 mg twice daily, geometric mean Cmax of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 66% and 69%, and AUC0-∞ about 82% and 79%, of those after amenamevir alone. (3) Ritonavir (inhibitor of CYP3A): When given with single doses of ritonavir 600 mg, geometric mean Cmax of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 1.4 and 1.6 times higher, and geometric mean AUC0-∞ about 2.6 and 3.3 times higher, than after amenamevir alone. Amenamevir has the potential to be involved in CYP3A-mediated pharmacokinetic interactions in clinical practice.

Utilization of data below the analytical limit of quantitation in pharmacokinetic analysis and modeling: promoting interdisciplinary debate.

Traditionally, bioanalytical laboratories do not report actual concentrations for samples with results below the LOQ (BLQ) in pharmacokinetic studies. BLQ values are outside the method calibration range established during validation and no data are available to support the reliability of these values. However, ignoring BLQ data can contribute to bias and imprecision in model-based pharmacokinetic analyses. From this perspective, routine use of BLQ data would be advantageous. We would like to initiate an interdisciplinary debate on this important topic by summarizing the current concepts and use of BLQ data by regulators, pharmacometricians and bioanalysts. Through introducing the limit of detection and evaluating its variability, BLQ data could be released and utilized appropriately for pharmacokinetic research.

Amenamevir: Studies of Potential CYP2C8- and CYP2B6-Mediated Pharmacokinetic Interactions With Montelukast and Bupropion in Healthy Volunteers.

Amenamevir (formerly ASP2151) induces cytochrome P450 (CYP)2B6 and CYP3A4 and inhibits CYP2C8.  We conducted 2 studies, 1 using montelukast as a probe to assess CYP2C8 and the other bupropion to assess CYP2B6.  The montelukast study examined the effect of amenamevir on the pharmacokinetics of montelukast in 24 healthy men: each subject received montelukast 10 mg alone, followed by montelukast 10 mg with amenamevir 400 mg, or vice versa after a washout period.  In the bupropion study, 24 subjects received a single dose of 150 mg bupropion on days 1, 15, 22, and 29, and repeated once-daily doses of 400 mg amenamevir on days 6-15.  Amenamevir increased peak concentration and area under the concentration-time curve of montelukast by about 22% (ratio 121.7%, 90%CI [114.8, 129.1]; 121% [116.2, 128.4], respectively) with a similar increase in hydroxymontelukast (ratio 121.4%, 90%CI [106.4, 138.5]; 125.6 % [111.3, 141.7]).  Amenamevir reduced peak concentration and area under the concentration-time curve of bupropion by 16% (84.29%, 90%CI [78.00, 91.10]; 84.07%, 90%CI [78.85, 89.63]), with recovery after 1 week; the pharmacokinetics of the primary metabolite hydroxybupropion was unaffected.  Thus, amenamevir increased plasma concentrations of montelukast and decreased those of bupropion, but it did not do so enough to require dose adjustment of coadministered substrates of either CYP2C8 or CYP2B6.