Pharmacokinetic interaction between regorafenib and atorvastatin in rats.

BACKGROUND: Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug-drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites. METHODS: Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (IREG+ATO), a carrier with regorafenib (IIREG), and atorvastatin with a carrier (IIIATO). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model. RESULTS: A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the IREG+ATO group, the Cmax, AUC0-t, and AUC0-∞ of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the Cmax, AUC0-t, and AUC0-∞ of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC0-t and AUC0-∞ of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively. CONCLUSIONS: This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.

Analgesic Efficacy of Oxycodone in Postoperative Dressings after Surgical Treatment of Burn Wounds: A Randomised Controlled Trial.

INTRODUCTION: This study aimed to assess the analgesic efficacy of oxycodone at doses of 10 mg and 20 mg in dressings after surgery of burn wounds. MATERIAL AND METHODS: Twenty adult patients who underwent surgical treatment of third-degree burn wounds under general anaesthesia were included. Burn wounds were treated with dressings, to which oxycodone was added at 20 mg in Group 1 and 10 mg in Group 2. After the surgery, plasma oxycodone and noroxycodone concentrations were assayed, and pain intensity was assessed with Numerical Rating Scale (NRS). RESULTS: In Group 1, no patient reported pain; in Group 2, four patients reported pain. The pain intensity, according to NRS, was 1-8. Plasma concentration of oxycodone in the blood serum was in the range of 1.24-3.15 ng/mL and 1.09-1.28 ng/mL in Group 1 and Group 2, respectively. Noroxycodone was not detected in the plasma. Adverse effects were not observed in any of the treated patients. CONCLUSIONS: Oxycodone in dressings provides patients with adequate and safe analgesia.

Bidirectional pharmacokinetic drug interactions between olaparib and metformin.

OBJECTIVE: Olaparib is a PARP (poly-ADP-ribose polymerase) inhibitor used for maintenance therapy in BRCA-mutated cancers. Metformin is a first-choice drug used in the treatment of type 2 diabetes. Both drugs are commonly co-administered to oncologic patients with add-on type 2 diabetes mellitus. Olaparib is metabolized by the CYP3A4 enzyme, which may be inhibited by metformin through the Pregnane X Receptor. In vitro studies have shown that olaparib inhibits the following metformin transporters: OCT1, MATE1, and MATE2K. The aim of the study was to assess the influence of 'the perpetrator drug' on the pharmacokinetic (PK) parameters of 'the victim drug' after a single dose. To evaluate the effect, the AUC0→∞ (area under the curve) ratio was determined (the ratio between AUC0→∞ in the presence of the perpetrator and AUC0→∞ without the presence of the perpetrator). METHODS: Male Wistar rats were assigned to three groups (eight animals in each group), which were orally administered: metformin and olaparib (IMET+OLA), vehiculum with metformin (IIMET), and vehiculum with olaparib (IIIOLA). Blood samples were collected after 24 h. HPLC was applied to measure the concentrations of olaparib and metformin. The PK parameters were calculated in a non-compartmental model. RESULTS: Metformin did not affect the olaparib PK parameters. The AUC0→∞ IMET+OLA/IIIOLA ratio was 0.99. Olaparib significantly increased the metformin Cmax (by 177.8%), AUC0→t (by 159.8%), and AUC0→∞ (by 74.1%). The AUC0→∞ IMET+OLA/IIMET ratio was 1.74. CONCLUSIONS: A single dose of metformin did not affect the PK parameters of olaparib, nor did it inhibit the olaparib metabolism, but olaparib significantly changed the metformin pharmacokinetics, which may be of clinical importance.

Analgesic Efficacy and Safety of Spinal Oxycodone in Total Hip Arthroplasty: A Preliminary Study.

AIM: The aim of this study was to assess the analgesic efficacy and safety of 1 mg and 0.5 mg oxycodone administration in a spinal block procedure for a total hip arthroplasty (THA). PATIENTS AND METHODS: Forty-two THA patients aged 59-81 with American Society Anesthesiology (ASA) II-III were included. All patients received anesthesia using spinal blockade, with bupivacaine 0.5% spinal heavy 2.5 ml, with 0.5 ml oxycodone hydrochloride 1.0 mg (group A; n = 28) or 0.5 mg (group B; n = 14). During surgery, each patient was sedated with 2-4 mg/kg/h intravenous propofol infusion. They received 100 mg intravenous ketoprofen at the end of the surgery at 8 pm and 8 am, with recommended doses every 12 h thereafter. Subcutaneous morphine 5 mg was used as a rescue analgesic, and the time to morphine use was recorded. After surgery, pain intensity (at the moment of patient report) was assessed using an 11-point numerical rating scale (NRS). The incidence of adverse effects was monitored. Blood samples were taken for assays of serum oxycodone, noroxycodone and bupivacaine levels. RESULTS: The time to rescue analgesia was 9.6 ± 5.6 h in group A and 7.3 ± 1.9 h in group B, and it did not differ between patient groups (P = 0.179). The mean NRS pain score was 4.5 in group A and 4.2 in group B. Three group A patients had detectable oxycodone levels: two < 7.1 ng/ml and in 1 spinal block induced anesthesia was unsuccessful and so he/she underwent general anesthesia (this patient was excluded from the analysis). Four group B patients had single values < 5 ng/ml. Noroxycodone levels were in all patients undetectable, and bupivacaine levels were 70-300 ng/ml. Regarding adverse effects, one patient had hypotension, one had bradycardia, and one had pruritus. CONCLUSION: Oxycodone in spinal block prolongs analgesia period, does not cause serious adverse effects and seems to be safe and effective opioid for patients undergoing THA.

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats.

A combination of the tyrosine kinase inhibitor-sorafenib-and the opioid analgesic-morphine-can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug-drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC0-t, and AUC0-∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0-t of its active metabolite-sorafenib N-oxide-was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0-t, and AUC0-∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of New Anti-Migraine Drugs-Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies.

In the last few years, there have been significant advances in migraine management and prevention. Lasmiditan, ubrogepant, rimegepant and monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) are new drugs that were launched on the US pharmaceutical market; some of them also in Europe. This publication reviews the available worldwide references on the safety of these anti-migraine drugs with a focus on the possible drug-drug (DDI) or drug-food interactions. As is known, bioavailability of a drug and, hence, its pharmacological efficacy depend on its pharmacokinetics and pharmacodynamics, which may be altered by drug interactions. This paper discusses the interactions of gepants and lasmiditan with, i.a., serotonergic drugs, CYP3A4 inhibitors, and inducers or breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) inhibitors. In the case of monoclonal antibodies, the issue of pharmacodynamic interactions related to the modulation of the immune system functions was addressed. It also focuses on the effect of monoclonal antibodies on expression of class Fc gamma receptors (FcγR).

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats.

The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib-metformin and sorafenib-atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2-hydroxy atorvastatin (p = 0.0239) and 4-hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.

Rectal enema of bupivacaine in cancer patients with tenesmus pain - case series.

Introduction: Rectal tenesmus pain in cancer patients most frequently appears in patients with colon cancer, and as a consequence of radiotherapy of the hypogastrium region. Treatment with opioids and adjuvant analgesics is often ineffective. Patients and methods: Here, we report on two female patients diagnosed with colon and ovary cancer, respectively, who had very severe tenesmus pain (numerical rating scale 8-10) despite using high doses of opioids, including methadone with corticosteroids, anticonvulsants, antidepressants and ketamine. Results: In both patients, bupivacaine was administered via a rectal enema. In the first patient, bupivacaine was administered at a dose of 100 mg 0.1% (100 mL), and subsequently 100 mg 0.2% (50 mL), leading to effective analgesia for 8 and 12 hrs, respectively. In the second patient, 100 mg 0.1% (100 mL) was initially administered, followed by 100 mg 0.2% (50 mL), leading to effective analgesia for 12 and 17 hrs, respectively, with only dull abdominal pain reported that was relieved by 100 mg IV ketoprofen and complete disappearance of tenesmus pain. Rectal bupivacaine administration did not cause neurologic adverse effects, heart function disturbances or decreased blood pressure. A volume of 50 mL was enough to cover a painful area in the colon. Initial bupivacaine concentrations in the blood serum did not exceed 50 ng/mL and eventually dropped to 20 ng/mL and below. Conclusions: Administration of 100 mg bupivacaine as a rectal enema is safe and provides effective analgesia, and this procedure may be conducted in hospital departments and out-patient clinics. Furthermore, this procedure in the case of pain recurrence, can be repeated, and by providing effective pain relief often allows time for the patient to be transferred to a specialized pain center.

The influence of a single and chronic administration of venlafaxine on tramadol pharmacokinetics in a rabbit model.

BACKGROUND: The combined use of tramadol with selective serotonin and norepinephrine reuptake inhibitors e.g. venlafaxine may be associated with serotonin syndrome. No previous studies exist examining the influence of a weak CYP2D6 inhibitor venlafaxine on the pharmacokinetics of tramadol. Therefore, the aim of this study was to determine the effect of a single and chronic administration of venlafaxine on the pharmacokinetics of tramadol using a rabbit model. METHODS: Adult New Zealand white rabbits of both sexes (n=21) were used. Animals received 100mg of tramadol per os (one slow release tablet) and 75mg of venlafaxine (one prolonged release capsule), and were divided into four groups: control group - a single dose of tramadol alone, 1day group - a single dose of tramadol and venlafaxine, 7 and 14days groups - seven and fourteen days administration of venlafaxine once daily plus a single dose of tramadol on the last day of the study. RESULTS: Venlafaxine administration over a period of 7 and 14days resulted in faster elimination of tramadol compared to the control group: significantly higher values of k el, and lower values of t1/2kel and MRT for the 7 and 14days group were observed. Although no differences in bioavailability of tramadol were obtained. CONCLUSION: Using a rabbit model, there is no evidence that the combined administration of tramadol and venlafaxine may increase the plasma exposure of tramadol and therefore increase the risk of serotonin syndrome.

Coadministration of tramadol with aripiprazole and venlafaxine--The effect on spatial memory functions in male rats.

BACKGROUND: The impairment of memory functions is very common in patients with chronic pain, particularly in patients with existing cognitive disorders. Results of some studies confirmed that tramadol (TRM), a frequently prescribed analgesic drug, improves memory functions in humans. However, there are no studies on the effect of co-administration of TRM with antidepressants or antipsychotics on memory; therefore, the aim of this study was to evaluate the effect of concomitant use of TRM with a second generation antipsychotic-aripiprazole (ARI) and an antidepressant-venlafaxine (VEN) on memory using an animal model. METHODS: The effect of TRM (5mg/kg)+ARI (1.5mg/kg) and TRM (5mg/kg)+VEN (20mg/kg) on memory in Wistar rats was examined using the Morris water maze test after single and chronic administration (7 and 14 days). RESULTS: It was observed that a single and chronic administration of TRM, VEN or ARI alone, but not a combination of TRM+VEN or TRM+ARI (except for 14 days of treatment) can improve memory in rats compared to the control group. After 14 days of administration, both combinations achieved improvement similar to each drug individually and improved spatial memory in rats compared to the control animals. CONCLUSION: It can be assumed that chronic treatment with combinations of TRM+VEN or TRM+ARI is unlikely to cause memory impairment and interfere with either any antidepressant effect of VEN or any antipsychotic effect of ARI in patients suffering from chronic pain using TRM.

Effects of Low-Dose Escherichia coli Lipopolysaccharide-Induced Endotoxemia on Morphine Pharmacokinetics in an Animal Model.

OBJECTIVE: Systemic inflammation may change the bioavailability and pharmacokinetics of opioids. However, there are insufficient data on morphine pharmacokinetics in mild inflammatory conditions. This study aimed to determine the pharmacokinetics of morphine during low-dose endotoxemia in rabbits. DESIGN: In two experiments (separated by a 14-day washout period), 10 rabbits received intravenous morphine at a dose of 3 mg/kg. In the second set of experiments, morphine infusion was preceded by low-dose endotoxemia induced with lipopolysaccharide (Escherichia coli 0111: B4) at a dose of 5 µg/kg. The kinetics of systemic morphine concentrations and chosen physiological parameters were measured at specific time intervals up to 6 hours after morphine administration. RESULTS: In endotoxemia, decreased elimination half-life (P = 0.017), mean residence time (P = 0.022), and volume of distribution (P = 0.037) as well as an increased elimination rate constant (P = 0.013) and total body clearance (P = 0.023) were noted. The inverse linear correlation between morphine clearance versus the percentage (%) change in body temperature and pulse rate observed under control conditions was abolished under endotoxemia. CONCLUSIONS: Low-dose endotoxemia is correlated with significant alterations in morphine pharmacokinetics in rabbits, leading to the faster elimination of the drug. CLINICAL IMPLICATIONS: These findings may have important implications in patients with low-grade inflammation and imply the need to modify morphine dosing regimens to ensure optimal analgesia. The issue warrants further experimental and clinical investigation.

Biopharmaceutical evaluation of new slow release tablets obtained by hot tableting of coated pellets with tramadol hydrochloride.

This study was aimed at a biopharmaceutical evaluation of a new oral dosage form of tramadol hydrochloride (TH)--slow release tablets obtained by hot tableting of coated pellets, 100 mg (TP), compared to the conventional slow release tablets, Tramal Retard, 100 mg (TR). Both TP and TR formulations showed a similar release profile of TH (f2 was 71) in in vitro release studies. The in vivo study was a two-treatment, two-period, two-sequence, single-oral dose 100 mg, crossover design using rabbit model with the phases separated by a washout period of 14 days. It was shown that the amount of TH absorbed into the systemic circulation is similar for TP and TR (the 90% confidence intervals for the AUC(0-1), AUC(0-infinity) and ratios were 85-122 and 92-107%, respectively). However, after administration of slow release tablets obtained by hot tableting of coated pellets, a prolonged absorption and elimination processes and a smoother and more extended plasma profile of TH were observed. It can be assumed that the use of a new oral dosage form of TH in patients affects the extension of analgesia after single administration of the drug, with its gradual absorption into the systemic circulation.

In vitro - in vivo evaluation of a new oral dosage form of tramadol hydrochloride--controlled-release capsules filled with coated pellets.

The aim of this study was an in vitro - in vivo evaluation of a new oral dosage form of tramadol hydrochloride (TH), controlled-release capsules filled with coated pellets, 100 mg (TC), compared to the sustained release tablets, Tramal Retard, 100 mg (TR). In vitro release study of both formulations showed a similar release profile of TH over 8 h (f2 was 52). In vivo study (single oral, 100 mg dose administration in 8 rabbits) showed that the amount of TH absorbed into the systemic circulation after TC and TR administration was also similar (90% CI for AUC(0-t) and AUC(0-infinity) were 90-124% and 97-109%, respectively). However, a comparison of AUC(0-t) of pharmacokinetics of TC and TR indicates significantly prolonged absorption and elimination processes of TH when the drug is given in controlled-release capsules filled with coated pellets. It was manifested by longer: mean absorption time (p = 0.0016), mean residence time (p = 0.0268), absorption half-life (p = 0.0016), elimination half-life (p = 0.0493) and lower: absorption rate constant (p = 0.0016), elimination rate constant (p = 0.0148) and total body clearance Cl/F (p = 0.0076). It may be concluded that the new TH formulation could be expected to have a more prolonged analgesic activity than commercial sustained release tablets.

Concomitant use of tramadol and venlafaxine - evaluation of antidepressant-like activity and other behavioral effects in rats.

BACKGROUND: The aim of this study was to evaluate antidepressant-like effect (Porsolt test), locomotor activity and motor coordination of joint administration of tramadol (TRM) and venlafaxine (VEN) in rats. METHODS: The tests were performed on male Wistar rats after single and chronic treatment (7 and 14 days) with TRM intraperitoneally (ip) and VEN orally (po) administered once a day. The controls were given 0.5% carboxymethylcellulose (CMC) solution (0.5 ml per rat, ip and po). RESULTS: It was found that combination of TRM (5 mg/kg ip) with VEN (20 mg/kg po) caused an increased antidepressant effect compared to TRM and VEN administered alone, with no effect on locomotor activity or motor coordination in rats, which may be of clinical significance. It was also observed that reduced time of active swimming of animals in Porsolt test with an increased dose (10 and 20 mg/kg) and time of administration (7 and 14 days) of TRM were correlated with a decreased locomotor activity in rats. It may indicate the development of tolerance to TRM's antidepressant effect in rats during chronic treatment with doses higher than 5 mg/kg. CONCLUSION: It can be expected that combination of low doses of TRM and VEN could potentially be feasible and relatively safe in cases with acute pain with co-existing depression, however, further investigations are needed.

Intermittent subcutaneous morphine regimen for postoperative pain management following abdominal hysterectomy regarding morphine- and beta-endorphin systemic concentrations.

OBJECTIVES: Systemic ß-endorphin, an endogenous opioid and stress hormone, has been demonstrated to correlate with the postoperative pain intensity, however its putative role as a postoperative pain biomarker has not been cleared. METHODS: Thirty patients scheduled for elective hysterectomy were included into the study. Postoperative pain was assessed by a numeric rating scale from 0 to 10. Plasma morphine concentrations were determined using high performance liquid chromatography with UV detection. Plasma ß-endorphin concentrations were measured by a radioimmunoassay. RESULTS: Administration of morphine in intravenous infusion turned out to be a markedly better method of morphine administration up to 4th hour postoperatively regarding both drug concentration and pain rating. A significant correlation between systemic ß-endorphin concentration and pain rating at the 4th postoperative hour was found. No association between morphine and ß-endorphin concentrations was detected. CONCLUSION: Systemic ß-endorphin is not an appropriate pain marker in postoperative gynaecologic patients.

HPLC-UV determination of morphine in human plasma and its application to the clinical study.

A sensitive and specific high-performance liquid chromatography method with ultraviolet detection (HPLC-UV) has been developed for the quantification of morphine sulfate [(5alpha,6alpha)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol], (CAS: 52-26-6) in human plasma. The analyte was extracted from plasma samples with chloroform - isopropyl alcohol (90:10, v/v) and analyzed on a Bondapak C18 column. The calibration curves were linear within the range of 10-150 ng/mL. The lower limit of quantitation was 10 ng/mL with 0.5 mL plasma sample. The mean recovery of the drug from plasma samples was 83.39%. The results from analysis of quality-control samples at concentrations of 30, 75, and 150 ng/mL were indicative of good accuracy and precision. This method was successfully used to analyze morphine in plasma samples of patients after abdominal hysterectomy.

[The role of phytoestrogen therapy in relieving postmenopausal symptoms]. / Rola terapii fitoestrogenowej w lagodzeniu dolegliwosci u kobiet po menopauzie.

Side effects and contraindications connected with hormonal replacement therapy in climacterium resulted in search for new methods of softening menopausal symptoms. The aim of the following study was to evaluate, based on literature analysis, the effectiveness of phytohormonal therapy as an alternative method of relieving the symptoms of menopausal period and preventing the diseases connected with deficiency of estrogens after menopause. Phytoestrogens therapy reduces the number and strength of the vasomotor symptoms and improves serum lipid profile. Moreover phytoestrogens show beneficial effects on bone tissue metabolism, skin and mucous membranes condition and are applicable in chemoprevention. This therapy is an effective method, allowing to avoid further changes in blood and urogenital systems, which result from estrogen stimulation deficiency. Phytoestrogens administration is an efficient method of relieving postmenopausal symptoms, facilitating the difficult menopausal period and keeping good health condition.

Comparative bioavailability study of two ibuprofen preparations after oral administration in healthy volunteers.

The bioavailability of a new ibuprofen (2-(p-isobutylphenyl)propionic acid, CAS 15687-27-1) preparation was compared with a reference preparation of the drug in 23 healthy male volunteers, aged between 19 and 27. A single dose of 400 mg was given orally in the fasted state, using a randomized two-way crossover study. A washout period of two weeks separated both treatment periods. Ibuprofen plasma levels were determined by means of a validated HPLC method (UV detector). Values of 154.48 +/- 53.27 microg x h/ml (95 % confidence interval CI: 133.50-177.03) for the test, and 140.86 +/- 44.82 microg x h/ml (95% CI: 122.53-159.16) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum plasma concentrations Cmax of 39.53 +/- 7.11 microg/ml (95 % CI: 35.97-41.78) and 37.71 +/- 8.67 microg/ml (95% CI: 33.37-40.46) achieved for the test and reference preparations did not differ significantly. AUC(0-infinity) and Cmax ratios (90% CI) were within the 80-125% interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new ibuprofen preparation is therapeutically equivalent to the reference preparation for both, the extent and the rate of absorption, after single dose administration in healthy volunteers.