A pharmacokinetic study investigating the rate of absorption of a 500 mg dose of a rapidly absorbed paracetamol tablet and a standard paracetamol tablet

ABSTRACT

Objective: A rapidly absorbed tablet formulation of paracetamol containing sodium bicarbonate (PS) has been previously shown to be absorbed at least twice as fast as a standard paracetamol tablet (P) at a 1?g dose. In South America and Asia it is customary for patients to take a 500?mg dose of analgesic. The objective of this pharmacokinetic study was to compare the rate of absorption of PS versus P at a 500?mg dose.

Research design and methods: An open, randomized, single dose, cross-over study. Thirty Hispanic healthy volunteers randomly received a 500?mg dose taken orally with 50?mL of water 2?h after a standard breakfast. Blood samples were taken up to 10?h post-dose. Plasma concentrations of paracetamol were determined by HPLC with UV detection.

Main outcome measures: AUC_{0–30 min}, C_{plasma 30 min} and T_max were analyzed non-parametrically by the Wilcoxon's rank sum test. A linear mixed effects model was used to analyze the logarithmically transformed AUC_0–∝ and C_max. Bioequivalence was accepted if the 90% confidence intervals (CI) for the ratio of the means of the primary pharmacokinetic variable AUC_0–∝ lay completely within the range 0.80–1.25.

Results: AUC_{0–30 min} and C_{plasma 30 min} were significantly greater and T_max was significantly shorter (all p < 0.0001) for PS versus P. The formulations were bioequivalent for AUC_0–∝ (90% CI 0.99:1.05) and no statistical difference was seen for C_max (95% CI 0.91:1.14).

Conclusions: Paracetamol was absorbed at least twice as fast from PS compared to P at a 500?mg dose. The extent of absorption was equivalent for both formulations.     

Assessing the viability of long-acting β2-agonists in paediatric asthma patients: a pharmacokinetic/pharmacodynamic perspective

Introduction: Long-acting β₂-agonists (LABAs) combined with inhaled corticosteroids (ICSs) are still commonly prescribed to asthmatic children. Unfortunately, pediatric LABA use is based primarily on data from adults, despite the fact that children are not simply small adults and the magnitude of changes in dose exposure and/or exposure response may not be solely reflected by differences in body weight.

Areas covered: The differences in pharmacokinetics (PK) and pharmacodynamics (PD) of LABAs are described and discussed with reference children and adults.

Expert opinion: Data on the PK behavior of LABAs is very limited and there is almost no data on once-daily LABAs available in the pediatric population. We do not believe that this is due to a fundamental lack of information because therapeutic response and adverse effects are more useful for the optimization of β₂-agonist treatment than measurement of plasma drug concentrations per se. Nevertheless, population PK-PD studies in children are needed according to the European rules in order to define rational, patient-tailored dosing schemes. Population PK-PD modeling and simulation using non-linear mixed effect modeling should be considered as the preferred tool to develop effective and safe dosing regimens for children because they present an opportunity to analyze sparse and unbalanced datasets, thereby minimizing the burden for each child.     

A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors

Summary Purpose To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients. Experimental design Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m²/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000. Results Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug–drug interactions. Conclusions Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m²/day. Work previously presented in part at the Annual Conference of the American Society for Clinical Oncology, Chicago, IL, 2003.     

Should patients skip late doses of medication? A pharmacokinetic perspective

Journal of Pharmacokinetics and Pharmacodynamics - Missed doses, late doses, and other dosing irregularities are major barriers to effective pharmacotherapy, especially for the treatment of chronic...     

Costs,quality of life,treatment satisfaction and compliance in patients with β-thalassemia major undergoing iron chelation therapy: the ITHACA study

ABSTRACT

Objectives: Iron chelation treatment (ICT) in β-thalassemia major (β-TM) patients undergoing blood transfusions can cause low satisfaction, low compliance, with possible negative consequences on treatment success, patients' wellbeing, and costs. The purpose was to estimate the societal burden attributable to β-TM in terms of direct and indirect costs, health-related quality-of-life (HRQoL), satisfaction and compliance with ICT in patients undergoing transfusions and ICT.

Research design and methods: The naturalistic, multicenter, longitudinal Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) cost-of-illness study was conducted involving patients of any age, on ICT for at least 3 years, who were enrolled at 8 Italian Thalassemia Care Centers. Costs were estimated from the societal perspective, quantified with tariffs, prices, or net earnings valid in 2006.

Results: One-hundred and thirty-seven patients were enrolled (median age = 28.3, 3–48 years, 49.6% male) and retrospectively observed for a median of 11.6 months. Mean direct costs were €1242/patient/month, 55.5% attributable to ICT, 33.2% attributable to transfusions. Relevant quantity and quality of productivity was lost. Both physical and mental components of HRQoL were compromised. Little difficulties remembering to take ICT and positive satisfaction with the perceived effectiveness of therapy were declared, but not good levels of satisfaction with acceptance, perception of side effects and burden of ICT.

Conclusions: The management of β-TM patients undergoing transfusions and ICT is efficacious, although costly, but overall benefits were not always perceived as optimal by patients. Efforts must be focused to improve patients' acceptance and satisfaction with their therapy; this would contribute to a better compliance and hence an increase in treatment effectiveness and patients' overall wellbeing, with expected improved allocation of human and economic resources.     

A pharmacokinetic–pharmacodynamic model for intrathecal baclofen in patients with severe spasticity

Aims

Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic–pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB.

Methods

Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 μg and an optional dose of 100 μg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model.

Results

All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 μg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed‐effect model.

Conclusions

ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level.     

Determination of oxaceprol in rat plasma by LC–MS/MS and its application in a pharmacokinetic study

A sensitive method for the quantification of oxaceprol in rat plasma using high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) was developed. Sample pretreatment involved a simple protein precipitation by the addition of 60 μL of acetonitrile–methanol (1:2, v/v) to 20 μL plasma sample volume. Separation was achieved on a Dikma ODS-C18 (5 μm, 150 mm × 4.6 mm) reversed-phase column at 40 °C with acetonitrile/0.1% formic acid–4 mM ammonium acetate in water (35:65,v/v) at a flow rate of 0.6 mL/min. Detection was performed using an electrospray ionization (ESI) operating in negative ion multiple reaction monitoring (MRM) mode by monitoring the ion transitions from m/z 172 → 130 (oxaceprol) and m/z 153 → 109 (protocatechuic acid, internal standard). The calibration curve of oxaceprol in plasma showed good linearity over the concentration range of 1.25–800 ng/mL. The limit of detection and limit of quantification were 0.400 ng/mL and 1.25 ng/mL, respectively. Intra- and inter-day precisions in all samples were within 15%. There was no matrix effect. The validated method was successfully applied to a preclinical pharmacokinetic study of oxaceprol in rats. After oral administration of 20 mg/kg oxaceprol to rats, the main pharmacokinetic parameters T_max, C_max, T_1/2, V_z/F and AUC_0–t were 1.4 h, 1.2 μg/mL, 2.3 h, 19.7 L/kg and 3.4 mg h/L, respectively.     

Are experiences of sexual violence related to special needs in patients with substance use disorders? A study in opioid-dependent patients

A history of sexual violence has been related to more complex treatment needs in patients with substance use disorders (SUD). Most of the existing studies, however, included patients with various types of SUD, did not examine gender differences and focused on a small range of clinical domains. Our sample consisted of opioid-dependent outpatients treated during a three-year period in a German metropolitan region. The analysis was based on a local case register and included all patients for whom information on lifetime sexual violence was available (N = 3531; 68.3% males). In a case–control design, patients with a history of sexual violence were compared to patients without these experiences regarding a wide range of clinical and social factors indicative of potential needs. Almost two thirds (65.6%) of the female patients and 10.9% of the males reported experiences of sexual violence. Victims differed from non-victims across a variety of domains, including more psychiatric symptoms and suicide attempts, more legal problems, financial and family problems, as well as a higher use of services. In contrast to a previous study among alcohol-dependent patients, no gender differences became apparent. Our findings suggest that experiences of sexual violence are an indicator for more complex needs in opioid-dependent patients of both genders. In addition to integrated trauma-informed approaches, an effort needs to be made to link addiction facilities to further institutions to meet these complex needs.     

Ochratoxin A and β2-microglobulin in BEN patients and controls

Ochratoxin A (OTA) is a mycotoxin naturally occurring in different foods. OTA is arguably a risk factor for Balkan endemic nephropathy (BEN). The aims of this study are to (1) test the OTA-BEN association in BEN-groups and controls and (2) determine whether urine β2-microglobulin, a marker of impaired ability of the kidneys to re-absorb, is related to OTA. BEN patients had significantly higher OTA serum levels. Within the offspring, OTA was significantly related to higher β2-microglobulin excretion. OTA (2005/2006) was related to a higher incidence of BEN after 2008, providing further evidence that OTA is a risk factor for BEN.     

Is auricular acupuncture beneficial in the inpatient treatment of substance-abusing patients? A pilot study

Patients with comorbid substance abuse problems who were admitted to a psychiatric unit of a general hospital over an 11-month period were offered treatment with auricular acupuncture. Subsequently and retrospectively, the medical records of these patients were examined to assess compliance, side effects, impact on course, and acceptance of discharge recommendations. Patient's continuation of treatment in destination programs was also followed. Seventy-seven patients were offered acupuncture: 30 patients refused or had four or fewer treatments (control group), and 47 had acupuncture five or more times (treatment group). The treatment group did significantly better than the control group as indicated by the following findings: compliance with psychiatric/substance abuse treatment on the unit was 75% in the treatment group vs. 20% in the control group, noncompliance or AMA discharge rate was 2% in the treatment group vs. 40% in the control group, acceptance of staff's discharge recommendations was 77% in the treatment group vs. 37% in the control group, and 58% of the treatment group patients remained in follow-up treatment for at least 4 months, vs. only 26% of the control group patients. Average inpatient length of stay was 22 days for the treatment group patients compared to 16 days for the control group patients. Side effects in the treated patients were negligible. Auricular acupuncture thus appears to be a safe and inexpensive treatment modality that is easily administered and produces significant results. Its wider application in substance abuse treatment appears warranted.     

Can finger-prick sampling replace venous sampling to determine the pharmacokinetic profile of oral paracetamol?

The drive to increase the availability of paediatric pharmacokinetic data with minimum blood loss has led to the development of micro-sampling techniques. However studies have suggested that pharmacokinetic data from venous or capillary blood samples may not be directly comparable.

AIM

The aim of this study was to determine whether paracetamol demonstrates concentration differences between finger-prick and venous blood samples.

METHODS

Paired finger-prick and venous blood samples were taken at 0, 15, 30 and 60 min following 1 g oral paracetamol, from 12 male adult subjects. Paracetamol concentration was determined using HPLC and UV detection with a LLOQ of 2200 pg on column. Intra-assay coefficient of variation for paracetamol at the LLOQ was 3%.

RESULTS

At 15, 30, and 60 min post dose the median finger-prick paracetamol concentration was 349%, 72%, and 9.3% greater than the equivalent venous concentrations, respectively. Regression analysis confirmed a significant relationship between finger-prick and venous paracetamol concentrations at 15 min (r² = 0.81, P = 0.006), at 30 min (r² = 0.82, P < 0.0001) and at 60 min (r² = 0.87, P < 0.0001) post dose. The regression equation for venous and finger-prick blood concentrations at 15, 30 and 60 min post dose were Venous₁₅ = Finger₁₅ − 3.4, Venous₃₀ = Finger₃₀ − 3.4 and Venous₆₀ = 0.68Finger₆₀ + 3.06, respectively.

CONCLUSIONS

Paracetamol demonstrates an arteriovenous difference in concentration, and the use of finger-prick samples may give rise to results which differ from those obtained with traditional venous sampling especially during the first 1 h following drug ingestion.     

Piperacillin/tazobactam as an alternative antibiotic therapy to carbapenems in the treatment of urinary tract infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae: an in silico pharmacokinetic study

Piperacillin/tazobactam (TZP) as an alternative treatment to carbapenems for infections involving extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) remains debated. In this study, the probabilities of pharmacodynamic (PD) target attainment with different TZP regimens in ESBL-producing Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp) were evaluated in the context of pyelonephritis. Minimum inhibitory concentrations (MICs) of 144 ESBL-Ec and 111 ESBL-Kp from pyelonephritis were measured, and two previously published population pharmacokinetic models were used to determine by Monte Carlo simulation the probabilities of reaching two PD targets (50%fT_>MIC and 100%fT_>MIC) with TZP doses of 4?g three times daily and 4.5?g four times daily given as short (1?h) or prolonged (4?h) infusions or as 12–18?g/day continuous infusions. Only MICs of the 133 ESBL-Ec and 74 ESBL-Kp strains susceptible to TZP according to inhibition zone diameter were considered for the simulations. Results were similar with the two models, and only prolonged and continuous infusions allowed to reach 50%fT_>MIC with a probability of >90% irrespective of bacterial species. Continuous infusion and prolonged infusion combined with the maximum dosage were the only condition allowing to achieve 100%fT_>MIC with a probability of >70% with this population of ESBL-Ec. A probability of >90% to reach 100%fT_>MIC with ESBL-Kp could be obtained only with the 18?g/day continuous-infusion regimen. TZP may be used for treatment for mild pyelonephritis involving susceptible ESBL-Ec provided that administration modalities are optimised. Conversely, for ESBL-Kp the risk of treatment failure may be higher, supporting the use of continuous infusion.     

A randomized,multicentric, comparative evaluation of aceclofenac–paracetamol combination with aceclofenac alone in Indian patients with osteoarthritis flare-up

Objective: To evaluate efficacy and safety of aceclofenac–paracetamol combination against aceclofenac alone in patients with osteoarthritis (OA) flare-up. Methods: This open, randomized, comparative, multicentric, 10-day study enrolled 199 patients (aceclofenac 100 mg + paracetamol 500 mg bid: 101; aceclofenac 100 mg, bid: 98) with painful OA flare-up. Primary efficacy parameters were pain intensity difference (PID), sum of PID (SPID), and peak PID over 4 h (0.5, 1, 2, 4 h) after first dose of study medication. Secondary efficacy measurements were mean pain intensity scores from day 1 to day 10, WOMAC scores, changes in baseline signs and symptoms, and patient's and investigator's overall efficacy assessment. Results: Both treatments showed significant improvement in their baseline values in all efficacy parameters. The combination was superior over monotherapy in terms of PID ( -0.54 vs -0.23, -1.23 vs -0.72, -1.73 vs -1.23 and -1.94 vs -1.43 at 0.5, 1, 2 and 4 h respectively), SPID ( -5.46 vs -3.63) and peak PID ( -2.08 vs -1.56; p < 0.05). At the end of therapy, both treatments were comparable (p > 0.05) with respect to average pain intensity from day 1 to day 10, changes in WOMAC scores and resolution of baseline signs and symptoms. The combination was significantly superior to monotherapy with respect to the patients' and investigators' overall efficacy assessments (p = 0.035 and p = 0.009 respectively). Conclusion: The findings of this open-label, comparative study in Indian patients demonstrates that aceclofenac–paracetamol combination is effective and well tolerated in relieving OA flare-up pain. The combination showed rapid pain relief compared with monotherapy which is desirable by such patients and, hence, this combination can play an important role in the management of acute painful OA flare-up.     

Does combining antiretroviral agents in a single dosage form enhance quality of life of HIV/AIDS patients? A cost-utility study

BackgroundCombining various antiretroviral agents into one single dosage form has been a strategy to reduce pill burden and enhance medication adherence among human immunodeficiency virus /AIDS (HIV/AIDS) patients.ObjectivesThis is a cost-utility study from a health care system’s perspective comparing coformulated fixed dose (FXD) strategy versus multiple free dose combination (FRC) in antiretroviral therapy.MethodThe Medical Expenditure Panel Survey (MEPS) was used to identify HIV/AIDS patients with ≥2 active antiretroviral medications. Patients on FXD were matched in 1:1 ratio with the FRC group using propensity scores. All medical costs excluding those paid by patients and families were included. Utility was measured using SF-6D scores from the SF-12 questionnaire. Incremental cost-utility ratios (ICURs) were calculated using the mean annual estimates. A cost-effectiveness acceptability curve was determined using a Monte Carlo probabilistic simulation technique.ResultsNine FXD antiretroviral formulations approved by the U.S. Food and Drug Administration by 2005 was included in this study. One hundred seventy HIV/AIDS patients with ≥2 antiretroviral agents were identified from the MEPS database, of which 53% (n = 92) were on FXD formulation. On matching, 70 patients from FXD had a match from the FRC group. No differences in sociodemographic and health status variables were observed between the matched groups. The mean annual cost was $15,766.15 for FXD patients and $11,875.21 for FRC patients. The mean utility gained by using FXD over FRC was 0.085; however, this difference was not statistically significant. The ICUR for the FXD treatment over FRC treatment was $45,540.49/quality-adjusted life years (QALYs). Probabilistic sensitivity analysis showed FXD to dominate FRC (>50% probability of being cost-effective) above the $40,000 threshold.ConclusionAlthough the cost-effectiveness of a single-pill strategy was within the acceptable willingness-to-pay threshold, the QALY difference were minimal. Further research is recommended to explore the long-term impact of the strategy.