The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

Background: Panadol Extend (PEx) is an over‐the‐counter, modified‐release formulation of paracetamol. Each 665 mg tablet contains 69% slow‐release and 31% immediate‐release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area‐under‐the‐curve (AUC) than comparable doses of immediate‐release paracetamol (APAP‐IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption. Objective: Do differences in pharmacokinetics (PK) between PEx and APAP‐IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol? Methods: Cross‐over study of 80 mg/kg of PEx or APAP‐IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24 h. Peak plasma concentration (Cmax), AUC_(0–∞), time to peak concentration (Tmax) and elimination half‐life (t_1/2) were compared. Results: PEx exhibited significantly lower paracetamol Cmax (252.33 µmol/L vs 565.56 µmol/L, P= 0.0421), AUC_(0–∞) (2133 µmol/h/L vs 2637 µmol/h/L, P= 0.0004) and delayed Tmax (2.889 h vs 1.389 h, P= 0.0189) than APAP‐IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP‐IR, showed similar AUC_(0–∞) (1369 µmol/h/L vs 1089 µmol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 µmol/L vs 95.889 µmol/L) and t_1/2 (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 µmol/L vs 335.22 µmol/L, P= 0.0239) than APAP‐IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected. Conclusion: There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx.     

Pharmacokinetic Effects of Diphenhydramine or Oxycodone in Simulated Acetaminophen Overdose

Objectives: To determine the effects of co‐ingested diphenhydramine (DPH) or oxycodone (OXY) on the absorption kinetics of simulated acetaminophen (APAP) overdose. Methods: This was an institutional review board–approved, prospective crossover study of ten healthy human volunteers ingesting 5 grams of APAP, 5 grams of APAP + 250 mg of DPH (APAP+DPH), or 5 grams of APAP + 0.5 mg/kg of OXY (APAP+OXY). Serum APAP concentrations (APAPs) were measured hourly from zero through eight hours and again at 24 hours, and basic noncompartmental pharmacokinetic parameters were compared. Results: For APAP alone, the mean parameters were: maximum APAP concentration ([APAP]_max) 71.8 μg/mL, time to peak [APAP] (t_max) 1.71 hours, and area under the receiver operating characteristic curve (AUC_0–8) 318.3 μg‐hr/mL. For APAP+DPH, the mean parameters were: [APAP]_max 67.6 μg/mL, t_max 1.90 hours, and AUC_0–8 297.7 μg‐hr/mL. For APAP+OXY, the parameters were: [APAP]_max 42.9 μg/mL, t_max 2.87 hours, and AUC_0–8 232.1 μg‐hr/mL. Compared with APAP alone, APAP+OXY had a 27% lower AUC, a 40% lower [APAP]_max, and a 68% longer t_max. Co‐ingested DPH had no significant effect on APAP absorption, except a 6% decrease in the AUC. Conclusions: Co‐ingested OXY, but not DPH, delayed absorption of APAP. This suggests a potential role for activated charcoal administration beyond one hour postingestion after mixed ingestions that include OXY.     

Acetaminophen psi parameter: A useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose

Context. The risk of hepatotoxicity secondary to acute acetaminophen overdose is related to serum acetaminophen concentration and lag time from ingestion to N-acetylcysteine (NAC) therapy. Psi (Greek letter ψ) is a toxicokinetic parameter that takes the acetaminophen level at 4 h post-ingestion ([APAP]_{4 h}) and the time-to-initiation of NAC (tNAC) into account and was found to be significantly predictive of hepatotoxicity in Canadian patients with acetaminophen overdose treated with intravenous NAC. Objective. We report the relationship of psi and hepatotoxicity in a Thai population with acute acetaminophen overdose. Methods. This is a retrospective study of patients with acute paracetamol overdose during January 2004 to June 2009 at Siriraj Hospital. Patients were treated with the standard 21-h intravenous NAC regimen. Univariate analyses were performed with logistic regression to assess the relationships of psi, [APAP]_{4 h}, and tNAC, and hepatotoxicity. Results. A total of 127 patients were enrolled. The median (interquartile range; IQR) of [APAP]_{4 h} was 267.8 (196.0–380.0) mg/L. The median (IQR) of tNAC was 8.5 (6.2–12.0) h. Thirteen patients (10.2%) developed hepatotoxicity. Univariate analysis revealed [APAP]_{4 h}, tNAC, and psi as statistically significant predictors of hepatotoxicity. Discussion and conclusion. The psi parameter is a reliable prognostic tool to predict hepatotoxicity secondary to acute acetaminophen overdose treated with intravenous NAC. Our evidence shows that psi may be a more superior tool than either acetaminophen level or time-to-initiation of NAC at predicting hepatotoxicity.     

External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose

Abstract

Context. Risk prediction in paracetamol (acetaminophen, or APAP) poisoning treated with acetylcysteine helps guide initial patient management and disposition. The paracetamol-aminotransferase multiplication product may be a useful and less time-sensitive risk predictor. Objective. The aim of this study was to validate this multiplication product in an independent cohort of patients with paracetamol overdose. Materials and methods. Using an existing toxicology dataset of poisoned patients from two large inner-city United Kingdom teaching hospitals, we retrospectively identified by electronic search all paracetamol overdoses from February 2005 to March 2013. We assessed the diagnostic accuracy of the multiplication product (serum APAP concentration × alanine transaminase [ALT] activity), especially at the pre-specified cut-off points of 1 500 mg/L × IU/L (10 000 micromol/L × IU/L) and 10 000 mg/L × IU/L (66 000 micromol/L × IU/L). The primary outcome was hepatotoxicity defined by a peak ALT > 1000 IU/L. Results. Of 3823 total paracetamol overdose presentations, there were 2743 acute single, 452 delayed single (> 24 h post overdose), 426 staggered (ingestion over > 1 h), and 202 supratherapeutic ingestions. Altogether, 34 patients developed hepatotoxicity. Among the acute single-ingestion patients, a multiplication product > 10 000 mg/L × IU/L had a sensitivity of 80% (95% confidence interval [CI]: 44%, 96%) and specificity of 99.6% [99.3%, 99.8%], while a product > 1 500 mg/L × IU/L had a sensitivity of 100% [66%, 100%] and specificity of 92% [91%, 93%]. Overall, 16 patients with a multiplication product > 10 000 mg/L × IU/L developed hepatotoxicity (likelihood ratio: 250, 95% CI: 130, 480), and 4 patients with a multiplication product between 1 500 and 10 000 (likelihood ratio: 2.5, 95% CI: 1.0, 6.0). No patient with a product < 1 500 mg/L × IU/L who received acetylcysteine developed hepatotoxicity. Conclusions. Regardless of ingestion type, a product > 10 000 mg/L × IU/L was associated with a very high likelihood, and < 1 500 mg/L × IU/L with a very low likelihood, of developing hepatotoxicity in patients treated with acetylcysteine.     

Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis

Context: The Rumack–Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. “Line-crossing” between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold.

Methods and materials: The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980–2005) following APAP poisoning. Population consisted of acute APAP overdose patients with at least two serum concentrations performed during hospitalization. Using ordinal logistic regression, we studied the effects of patient demographics, ingestion size/timing, APAP concentrations, time to N-acetylcysteine (NAC), and co-ingestants on a three-level dependent variable: patients whose risk increased two or more zones, those remaining in the same or adjacent zone, and those whose risk fell by two or more zones.

Results: Of the 3201 eligible hospitalizations with 7705 APAP concentrations, half (1679, 52.5%) crossed at least one zone (up or down) within 24?h of acute ingestion, including 190 (5.9%), who crossed at least two lines into a higher risk zone, and 516 (16.1%) at least two lines into a lower risk zone. Of the 1251 patients initially below the nomogram treatment line of 150?μg/mL, 131 (10.8%) patients crossed above this line. Being older, male, and co-ingesting opioids, antimuscarinics, or NSAIDs were independently associated with line-crossing.

Conclusions: Patients commonly crossed nomogram risk zones, including from below to above the current treatment threshold. These findings support recommendations for serial APAP testing until the individual risk of hepatic injury is clearly established.     

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

Background and objectives: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter‐individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods: Seventy‐six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non‐compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half‐life (t_1/2e), and area under the curve (AUC_0→∞). Results: One‐third of volunteers were smokers (n = 27) and one‐half had abnormal body weight (n = 39). Smokers had lower AUC_0→∞ (smokers: 6·24 ± 2·32 μg/h/mL vs. non‐smokers: 8·93 ± 3·80 μg/h/mL, P < 0·001) and shorter half‐life (smokers: 5·46 ± 2·99 vs. non‐smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on C_max (P = 0·3) and T_max (P = 0·7). There was no statistically significant difference in C_max, AUC_0→∞, T_max and t_1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter‐individual differences (C_max = 3·09 ± 0·99 μg/mL, CV = 32%), (T_max =0·76 ± 0·24 h, CV = 31·6%), (AUC_0→∞ = 7·98 ± 3·58 μg/h/mL, CV = 44·8%), and (t_1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking‐cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.     

Bupropion toxicokinetic: A case report

Context.?The toxicokinetics of sustained-release bupropion are not well described.?Case.?A 23-year-old Caucasian male took an overdose of 5,700 mg of sustained release bupropion with no co-ingestant. Venous serum samples were assayed for bupropion concentrations over the next 5 days. The peak concentration was 1.114 mg/L. The observed T_max was found to be 8.25 h, the calculated alpha half-life 10.9 h (±SE of 4.47%), and the calculated beta half-life 19.8 h (±SE 12.62%). The alpha half-life and T_max differ significantly from those seen in therapeutic doses.?Discussion.?Bezoar formation may underlie these differences. Interventions which reduce the absorption of sustained release bupropion may be effective in overdose.     

Microdose study of a P‐glycoprotein substrate,fexofenadine, using a non‐radioisotope‐labelled drug and LC/MS/MS

Objective: Fexofenadine is a P‐glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P‐glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic‐dose pharmacokinetics of fexofenadine from microdosing data using non‐radioisotope‐labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS). Method: In a single dose, randomized, two‐way crossover study, eight subjects received a microdose (100 μg) or a therapeutic dose (60 mg) of fexofenadine. Blood samples were collected until 12 h after dosing, and assayed using LC/MS/MS. Results: Plasma concentration–time curves of fexofenadine between microdose and therapeutic dose were similar. The mean ± SD of C_max normalized to 60 mg dose after microdose and therapeutic dose were 379 ± 147 and 275 ± 145 ng/mL respectively. The mean AUC_last normalized to 60 mg dose after microdose and therapeutic dose were 1914 ± 738 and 1431 ± 432 ng/h/mL respectively. The mean dose‐adjusted C_max and AUC_last after microdose were higher compared with those after therapeutic dose. Individual plots of C_max and AUC_last normalized to 60 mg dose, were similar for microdose and therapeutic dose. None of the pharmacokinetic parameters were statistically different using anova . Overall, the microdose pharmacokinetics profile was similar to, and hence predictive of, that of the therapeutic dose. Conclusion: For the P‐glycoprotein substrate fexofenadine, the predictability of therapeutic‐dose pharmacokinetics from microdose data was good. A microdose study using a non‐radioisotope‐labelled drug and LC/MS/MS is convenient, and has the potential to aid the early selection of drug candidates.     

Effect of glibenclamide on insulin release at moderate and high blood glucose levels in normal man

Insulin release occurs in two phases; sulphonylurea derivatives may have different potencies in stimulating first- and second-phase insulin release. We studied the effect of glibenclamide on insulin secretion at submaximally and maximally stimulating blood glucose levels with a primed hyperglycaemic glucose clamp. Twelve healthy male subjects, age (mean ± SEM) 22.5 ± 0.5 years, body mass index (BMI) 21.7 ± 0.6 kg m^?2, were studied in a randomized, double-blind study design. Glibenclamide 10 mg or placebo was taken before a 4-h hyperglycaemic clamp (blood glucose 8 mmol L^?1 during the first 2 h and 32 mmol L^?1 during the next 2 h). During hyperglycaemic clamp at 8 mmol L^?1, the areas under the Δinsulin curve (AUC_Δinsulin , mean ± SEM) from 0 to 10 min (first phase) were not different: 1007 ± 235 vs. 1059 ± 261 pmol L^?1 × 10 min (with and without glibenclamide, P = 0.81). However, glibenclamide led to a significantly larger increase in AUC_Δinsulin from 30 to 120 min (second phase): 16 087 ± 4489 vs. 7107 ± 1533 pmol L^?1 × 90 min (with and without glibenclamide respectively, P < 0.03). The same was true for AUC_ΔC-peptide: no difference from 0 to 10 min but a significantly higher AUC_ΔC-peptide from 30 to 120 min on the glibenclamide day (P < 0.01). The M/I ratio (mean glucose infusion rate divided by mean plasma insulin concentration) from 60 to 120 min, a measure of insulin sensitivity, did not change: 0.26 ± 0.05 vs. 0.22 ± 0.03 μmol kg^?1 min^?1 pmol L^?1 (with and without glibenclamide, P = 0.64). During hyperglycaemic clamp at 32 mmol L^?1, the AUC_Δinsulin from 120 to 130 min (first phase) was not different on both study days: 2411 ± 640 vs. 3193 ± 866 pmol L^?1 × 10 min (with and without glibenclamide, P = 0.29). AUC_Δinsulin from 150 to 240 min (second phase) also showed no difference: 59 623 ± 8735 vs. 77389 ± 15161 pmol L^?1 × 90 min (with and without glibenclamide, P = 0.24). AUC_ΔC-peptide from 120 to 130 min and from 150 to 240 min were slightly lower on the glibenclamide study day (both P < 0.04). The M/I ratio from 180 to 240 min did not change: 0.24 ± 0.04 vs. 0.30 ± 0.07 μmol kg^?1 min^?1 pmol L^?1 (with and without glibenclamide, P = 0.25). In conclusion, glibenclamide increases second-phase insulin secretion only at a submaximally stimulating blood glucose level without enhancement of first-phase insulin release and has no additive effect on insulin secretion at maximally stimulating blood glucose levels. Glibenclamide did not change insulin sensitivity in this acute experiment.     

Predicting acute acetaminophen hepatotoxicity with acetaminophen-aminotransferase multiplication product and the Psi parameter

Context. Prediction of potential hepatotoxicity is important for individualizing therapy with N-acetylcysteine (NAC) in patients with acute acetaminophen overdose. Acetaminophen-aminotransferase multiplication product (APAP × AT) and the Psi Parameter (Psi) have been reported to be the predictors of acetaminophen hepatotoxicity. Objective. To determine the validity of APAP × AT and Psi in predicting hepatotoxicity secondary to acute acetaminophen overdose. Materials and methods. We retrospectively reviewed acute acetaminophen overdose cases who were treated with NAC at Siriraj Hospital, Thailand during January 2004–June 2012. The patients’ ages were 12 years or more. Initial acetaminophen concentration (mg/L) and aminotransferase (IU/L) were multiplied to obtain APAP × AT. Psi were derived from initial acetaminophen concentrations (mg/L) and lag time (hours) to NAC therapy. The cut-off values for APAP × AT and Psi were 1500 mg?IU/L² and 5 mM?h, respectively. Hepatotoxicity (defined as aspartate or alanine aminotransferase (ALT) greater than 1000 IU/L) was the outcome of interest. Results. A total of 255 patients were included, 32 of whom developed hepatotoxicity. APAP × AT had sensitivity, specificity, and negative likelihood ratio of 90.6%, 62.8%, and 0.2, respectively. The sensitivity of Psi, specificity, and negative likelihood ratio were 96.9%, 91.5%, and 0.0, respectively. The areas under the curve of the receiver operating characteristic (ROC) curve for APAP × AT and Psi were 0.82 and 0.96, respectively, with a statistically significant difference between the two methods (p = 0.002). APAP × AT showed higher specificity (92.5%) in patients who presented 8–24 h after the overdose. Discussion and conclusion. Psi and APAP × AT are valid clinical tools in predicting hepatotoxicity secondary to acute acetaminophen overdose in adults. APAP × AT is useful in predicting a low likelihood of hepatotoxicity after standard NAC therapy among late-presenting patients.     

Impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning: The recent United Kingdom experience

Background. On 3 September 2012, the licensed indication for acetylcysteine was changed in the United Kingdom (UK) so that all patients with a plasma paracetamol concentration above a “100 mg/L” (4 h post ingestion) nomogram treatment line after an acute paracetamol (acetaminophen) overdose should be treated. This is a lower threshold than that used in the United States, Canada, Australia, and New Zealand. Here we report the impact of this change in the UK on the management of patients with acute overdose in different paracetamol concentration ranges. Methods. This is a cohort study, consisting of a retrospective analysis conducted on prospectively collected audit data in three UK hospitals. Following appropriate ethical and data protection authority approval, data for patients presenting within 24 h of an acute timed single paracetamol overdose were extracted. Numbers of admissions and use of antidote in relation to different paracetamol concentration bands (< 100 mg/L; 100–149 mg/L; 150–199 mg/L; and ≥ 200 mg/L at 4 h) were analyzed for one-year periods before and after the change. Results. Comparing the year before with the year after the change, there was no change in the numbers of patients presenting to hospital within 24 h of acute timed paracetamol overdose (1246 before and 1251 after), but more patients were admitted (759 before and 849 after) and treated with acetylcysteine (389 before and 539 after). Of the 150 additional patients treated with acetylcysteine in the year following the change, 114 (76%, 95% CI: 68.4–82.6) were in the 100–149 group and 9 (6.0%, 95% CI: 2.8–11.1) in the 150–199 group. Conclusions. Changes to national guidelines for managing paracetamol poisoning in the UK have increased the numbers of patients with acute overdose treated with acetylcysteine, with most additional treatments occurring in patients in the 100–149 mg/L dose range, a group at low risk of hepatotoxicity and higher risk of adverse reactions.     

Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets

What is known and Objective: Acarbose, an α‐glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. Methods: This investigation consisted of a pilot study and a main study. The pilot study had an open, single‐dose, single‐sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay^® 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two‐period, two‐sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100‐mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G_max) and the area under the serum glucose concentration–time profile (AUC_gluc) were determined and compared. Results and Discussion: Five subjects completed the pilot study. The AUC_gluc from dosing until 1 h post‐dose (AUC_{gluc,1 h}) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G_max (ΔG_max) and AUC_{gluc,1 h} (ΔAUC_{gluc,1 h}) for the reference formulation compared with placebo were 22·0 ± 18·3 mg/dL and 928·2 ± 756·0 mg min/dL, respectively. The corresponding values for the test formulation were 23·3 ± 21·2 mg/dL and 923·0 ± 991·4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for ΔG_max and ΔAUC_{gluc,1 h} were 1·06 and 1·00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0·79–1·39 and 0·64–1·36, respectively. What is new and Conclusion: The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0·80–1·25).     

Modified release paracetamol overdose: a prospective observational study (ATOM-3)

Background: Modified-release (MR) paracetamol is available in many countries as 665?mg tablets of which 69% is MR and 31% is immediate release. There are concerns that MR paracetamol overdose has higher rates of liver injury despite standard treatment algorithms. The objective of this study was to describe the clinical characteristics and outcomes of acute MR paracetamol overdose.

Methods: Prospective observational study, recruiting patients from January 2013 to June 2017, from five clinical toxicology units and calls to two Poisons Information Centres in Australia. Included were patients >14 years who ingested ≥10?g or 200?mg/kg (whichever is less) of MR paracetamol. Data collected included demographics, ingestion history, pathology results, treatments, and outcomes including hepatotoxicity (ALT >1000?U/L).

Results: In total, 116 patients were recruited, 85(73%) were female. The median dose ingested was 32?g (IQR: 20–49?g) and median time to presentation was 3?h (IQR: 2–9?h). 78(67%) had an initial paracetamol concentration above the nomogram line (150?mg/L at 4?h). A further 12(10%) crossed the nomogram after repeat paracetamol measurements, of which five crossed after two non-toxic levels 4?h apart. Six had a double paracetamol peak, in three occurring >24?h post-ingestion. 113(97%) received acetylcysteine of which 67 received prolonged treatment beyond the standard 21?h. This was because of an elevated paracetamol concentration at the completion of acetylcysteine in 39 (median paracetamol concentration 25?mg/L, IQR: 16–62?mg/L). 21 (18%) developed hepatotoxicity, including six treated within 8?h of ingestion. Activated charcoal and double doses of acetylcysteine did not significantly decrease the risk of hepatotoxicity.

Conclusions: Drug regulatory authorities are considering restrictions on MR paracetamol preparations. Following an acute MR paracetamol overdose, this study found that many patients had a persistently elevated paracetamol concentrations, many required prolonged treatment and some developed liver injury despite early acetylcysteine treatment. Furthermore, activated charcoal and increased acetylcysteine did not appear to significantly alter the risk of liver injury. Hence, research into better treatment strategies is required.

Trial registration: Australian Toxicology Monitoring (ATOM) Study – Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.     

Effect of levofloxacin on lithium – a pharmacokinetic study in rabbits

The aim of this study was to evaluate potential drug–drug interaction between lithium and levofloxacin. The study was conducted on New Zealand white rabbits with three groups having two subgroups each (n = 12). The first group compared the pharmacokinetic (Pk) parameters of lithium when lithium was given as a single dose (56 mg/kg) and when lithium was co‐administered with levofloxacin (35 mg/kg). The second group compared the Pk parameters of lithium when lithium was given for 6 days alone and when levofloxacin was given on the sixth day after lithium steady‐state levels were achieved. The third group compared the Pk parameters of lithium when lithium was given alone for 8 days and levofloxacin was given on days 6, 7, and 8 along with lithium. Apart from this, creatinine levels were also measured to detect nephrotoxicity effects because of this co‐administration. It was found that there was increase in lithium levels in all three groups. The increase was significant when a single dose of levofloxacin was administered with steady‐state level of lithium (C_max of lithium: 2.54 ± 0.15 vs 2.79 ± 0.12 mm , P < 0.001 and AUC_0‐α of lithium: 24.36 ± 3.68 vs 31.88 ± 4.83 mmol/mL h, P < 0.001). The increase in lithium levels was also significant when levofloxacin was coprescribed for 3 days after lithium steady‐state levels were achieved (C_max increased from 2.72 ± 0.29 to 3.96 ± 0.29 mm , P < 0.001 and AUC_0‐α increased from 27.1 ± 4.96 to 42.64 ± 4.94 mmol/mL h). Levofloxacin increases lithium levels when they are co‐administered, and this interaction might be clinically significant as they may be coprescribed.     

Paracetamol and opioid pathways: a pilot randomized clinical trial

Previous studies suggest that the antinociceptive action of paracetamol (acetaminophen, APAP) might involve descending inhibitory pain pathways and the opioidergic system: this study explores this issue in humans with naloxone, the opioid antagonist. After ethical approval, 12 healthy male volunteers were included in this randomized, controlled, double‐blind, crossover, four‐arm study. They were administered intravenous paracetamol (APAP 1 g) or saline (placebo, pl) followed at 100 min with IV naloxone (Nal 8 mg) or saline, every week for 4 weeks. The amplitude of cerebral potentials evoked by thermal/painful stimuli applied on the arm was recorded nine times over 150 min, witnessing of pain integration at central level. Amplitude changes as well as areas under the curve (AUCs) over 150 min were compared for the four treatments by repeated measures anova (significance 0.05). Amplitude changes were significant for APAP/pl vs. pl/pl at t₁₅₀: ?44% (95%CI ?58 to ?30) vs. ?27% (95%CI ?37 to ?17; P < 0.05) but not vs. APAP/Nal. AUC (0–150) of APAP/pl is significantly different from pl/pl (?3452%.min (95%CI ?4705 to ?2199) vs. ?933% min (95%CI ?2273 to 407; P = 0.015) but not from APAP/Nal (?1731% min (95%CI ?3676 to 214; P = 0.08) and other treatments. AUC (90–150) is not significantly different. This pilot study shows for the first time in human volunteers that naloxone does not inhibit paracetamol antinociception, suggesting no significant implication of the opioid system in paracetamol mechanism of action: this needs be confirmed on a larger number of subjects.     

A New Predictor of Toxicity Following Acetaminophen Overdose Based on Pretreatment Exposure

Introduction. Despite extensive clinical experience, no dose-response curve exists for acetaminophen toxicity in man. The absence of accurate toxicodynamics has hampered efforts to optimize patient therapy and to identify risk modifiers following overdose. We set out to parameterize both the degree and duration of pretreatment exposure into a single, continuous measure of exposure, which will serve as the x-axis of an eventual dose-response curve. Methods. The model was constructed from pharmacokinetic first principles, using as inputs the vertical distance above the Rumack-Matthew nomogram line (expressed as the equivalent serum acetaminophen concentration 4 h after ingestion) and the delay to antidote therapy (t_NAC). A no-effect dose ([APAP]_threshold) and lag time (t_i) were assumed. Results. The area under the serum acetaminophen concentration vs. time curve bounded by [APAP]_threshold, t_i and t_NAC represents our proposed time-weighted measure of exposure. We demonstrate that this non-negative area estimates the cellular burden of toxic adducts formed following overdose. This measure is also easily calculated at patient presentation using clinical data and allows for both declining serum acetaminophen concentrations and variable delays to antidote therapy. Discussion. We describe a new, pharmacokinetically based measure of exposure following acute acetaminophen overdose treated with N-acetylcysteine. Using this measure should enhance the analysis of nonexperimental clinical data and permit more accurate characterization of acetaminophen toxicodynamics. Ultimately, this approach may facilitate progress on many of the long-standing controversies regarding acetaminophen toxicity in man.     

Determination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokinetics

Objective: To develop a high performance liquid chromatography mass spectrometry (HPLC‐MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations. Methods: The GA in plasma was extracted with ethyl acetate, separated on a C₁₈ column with a mobile phase of methanol (5 mmol/L ammonium acetate)–water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469·5 for GA and m/z 455·6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively. Results: The calibration curve was linear over the range of 0·5–200 ng/mL (r = 0·9974). The limit of quantification for GA in plasma was 0·5 ng/mL, the recovery was 76·0–80·0%, and the inter‐ and intra‐day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t_1/2) 9·65 ± 3·54 h and 9·46 ± 2·85 h, the time to peak concentration (T_max) 10·95 ± 1·32 h and 11·00 ± 1·30 h, the peak concentration (C_max) 95·57 ± 43·06 ng/mL and 103·89 ± 49·24 ng/mL; the area under time‐concentration curve (AUC_0–48 and AUC_0–∞) 1281·84 ± 527·11 ng·h/mL and 1367·74 ± 563·27 ng·h/mL, 1314·32 ± 566·40 ng·h/mL and 1396·97 ± 630·06 ng·h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98·88 ± 12·98%. Conclusion: The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent.     

Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

What is known and objective: Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9‐hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug–drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. Methods: An open‐label, randomized, two‐phase crossover design with a 2‐week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2 mg of risperidone alone or in combination with 200 mg of ketoconazole, once daily for 3 days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96 h. Plasma concentrations of risperidone and 9‐hydroxyrisperidone were determined using a validated HPLC–tandem mass spectrometry method. Results and discussion: After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81 ± 15·10% and the T_1/2 of risperidone increased significantly by 28·03 ± 40·60%. The AUC_0–96 and AUC_0–∞ of risperidone increased significantly by 66·61 ± 43·03% and 66·54 ± 39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79 ± 53·59%. However, the C_max and T_max of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C_max, T_max and T_1/2 of 9‐hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9‐hydroxyrisperidone increased significantly by 135·07 ± 124·68%, and the Vd/f of 9‐hydroxyrisperidone decreased significantly by 29·47 ± 54·64%. These changes led to a corresponding significant decrease in the AUC_0–96 and AUC_0–∞ of 9‐hydroxyrisperidone by 47·76 ± 22·39% and 48·49 ± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. Our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. What is new and Conclusion: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.