Steady-state infusions of opioids in human. II. Concentration-effect relationships and therapeutic margins

We used computer-controlled individually tailored infusions to study relationships between plasma drug concentration and opioid effects, and to evaluate the therapeutic margins of alfentanil, fentanyl and morphine in human subjects. In order to compare the 3 drugs, we infused each opioid to 3 different steady-state target plasma concentrations during separate 8 h test periods so that concentration-effect curves could be defined for each opioid and subject. Dental electrical stimulation produced a consistent degree of baseline experimental pain, and we measured the influence of increasing plasma opioid concentrations on pain intensity and the magnitude of pain-related evoked potentials. We also quantified ventilatory function and subjective side-effects during baseline (no drug), at the 3 target plasma concentrations with each drug. Finally, we measured actual plasma opioid concentrations during each phase of the infusion period. This procedure allowed us to calculate for each opioid the plasma concentration required to produce a 50% decrease in reported pain intensity and evoked potential amplitude (IC50). Subsequent calculation of side-effect magnitudes at the analgesic IC50s permitted direct comparisons of therapeutic margins between alfentanil, fentanyl and morphine. We found a robust relationship between plasma drug concentration and analgesic, ventilatory, and subjective-effect magnitudes for each opioid in this study. We conclude that the magnitudes of individual side-effects associated with equianalgesic, steady-state plasma concentrations of these 3 mu receptor-selective opioids do not differ across drugs.     

Hypovolaemia after glucose/insulin infusions in volunteers

High-dose intravenous infusion of 5% glucose promotes rebound hypoglycaemia and hypovolaemia in healthy volunteers. To study whether such effects occur in response to glucose/insulin, 12 healthy firemen (mean age, 39 years) received three infusions over 1-2 h that contained 20 ml of 2.5% glucose/kg of body weight, 5 ml of 10% glucose/kg of body weight with 0.05 unit of rapid-acting insulin/kg of body weight, and 4 ml of 50% glucose/kg of body weight with 1 unit of insulin/kg of body weight. The plasma glucose concentration and plasma dilution were compared at 5-10 min intervals over 4 h. Regardless of the amount of administered fluid and whether insulin was given, the plasma glucose concentration decreased to hypoglycaemic levels within 30 min of the infusion ending. The plasma dilution closely mirrored plasma glucose and became negative by approx. 5%, which indicates a reduction in the plasma volume. These alterations were only partially restored during the follow-up period. A linear relationship between plasma glucose and plasma dilution was most apparent when the infused glucose had been dissolved in only a small amount of fluid. For the strongest glucose/insulin solution, this linear relationship had a correlation coefficient of 0.77 (n=386, P<0.0001). The findings of the present study indicate that a redistribution of water due to the osmotic strength of the glucose is the chief mechanism accounting for the hypovolaemia. It is concluded that infusions of 2.5%, 10% and 50% glucose, with and without insulin, in well-trained men were consistently followed by long-standing hypoglycaemia and also by hypovolaemia, which averaged 5%. These results emphasize the relationship between metabolism and fluid balance.     

Pharmacokinetic study of lenampicillin (KBT-1585) in healthy volunteers.

The pharmacokinetic properties of lenampicillin (KBT-1585), a new ampicillin ester, were investigated in 41 healthy volunteers. The maximum concentration of ampicillin in serum after oral administration of 400 mg of lenampicillin was 6.5 micrograms/ml at 0.70 h, and that after a equimolar dosage of ampicillin was 2.9 micrograms/ml at 0.87 h.     

Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers

OBJECTIVE: To assess the interaction between almotriptan, a 5-HT1B/1D-receptor agonist used to treat migraine, and verapamil, an agent for migraine prophylaxis. METHODS: Twelve healthy volunteers received the following treatments in a crossover design: (1) 120-mg sustained-release verapamil tablet twice daily for 7 days and one 12.5-mg almotriptan tablet on day 7 and (2) one 12.5-mg almotriptan tablet alone on day 7. Serial plasma and urine samples were obtained on day 7. Almotriptan plasma concentrations were determined by liquid chromatography-tandem mass spectrometry; urine samples were analyzed by ultraviolet HPLC. Safety measures included blood pressure and pulse measurements, electrocardiography, and adverse event monitoring. Statistical comparisons of pharmacokinetic parameters and vital sign data were made by ANOVA. RESULTS: Mean almotriptan peak concentration and area under the plasma concentration-time curve were significantly higher and volume of distribution and oral clearance were significantly lower after coadministration of almotriptan and verapamil compared with administration of almotriptan alone. The magnitudes of these differences were approximately 20%. Renal clearance was unaffected by verapamil coadministration. No significant effects of treatment on blood pressure or pulse were detected, with the exception of sitting systolic blood pressure at 2 hours after administration. However, the difference in mean change from baseline at this time point was only 8 mm Hg. CONCLUSIONS: Verapamil modestly inhibited almotriptan clearance to a degree consistent with the modest contribution of CYP3A4 to almotriptan metabolism. This observation and the lack of effect of verapamil on the tolerability to almotriptan administration suggest that no reduction of the almotriptan dose is warranted.     

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers

What is known and Objective: Ivabradine is a novel heart rate‐lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. Methods: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12‐h period following drug administration, using a high‐throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non‐compartmental and compartmental analysis to determine if there were statistically significant differences. Results and Discussion: In the two periods of treatments, the mean peak plasma concentrations (C_max) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C_max, t_max, were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC_0‐∞) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C_max and AUC_0‐∞ when ivabradine was administered with carbamazepine, whereas they were not for t_max, half‐life and mean residence time. What is new and Conclusion: TCarbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likley to be clinically significant.     

Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers

BACKGROUND: Praziquantel, a broad-spectrum anthelminthic, has been reported to undergo extensive first-pass metabolism by cytochrome P450 (CYP) enzymes in vivo. Ketoconazole, a potent CYP3A4 inhibitor, is known to markedly increase plasma concentrations of many co-administered drugs. However, no data are available on the potential pharmacokinetic drug interaction between ketoconazole and praziquantel in humans. OBJECTIVE: To investigate the potential pharmacokinetic interaction of ketoconazole with praziquantel in healthy adult Thai male volunteers. METHODS: In an open-label, randomized two-phase crossover study, separated by a 2-week period, 10 healthy adult Thai male volunteers ingested a single dose of 20 mg/kg praziquantel alone or with co-administration of 400-mg ketoconazole orally daily for 5 days. Venous blood samples were collected at specific times for a 24-h period. Plasma concentrations of praziquantel were determined using high-performance liquid chromatography. A non-compartmental model was applied for pharmacokinetic parameter analysis of praziquantel. RESULTS: Concurrent administration of ketoconazole with praziquantel significantly increased the mean area under the curve from time zero to infinity (AUC(0-alpha)) and maximum plasma concentration (Cmax) of praziquantel by 93% (955.94 +/- 307.74 vs. 1843.10 +/- 336.39 ng h/mL; P < 0.01) and 102% (183.38 +/- 43.90 vs. 371.31 +/- 44.63 ng/mL; P < 0.01), respectively, whereas the mean total clearance (Cl/F) of praziquantel was significantly decreased by 58% (2.65 +/- 0.64 vs. 1.11 +/- 0.35 mL/h/kg; P < 0.01). CONCLUSION: Ketoconazole co-administration alters the pharmacokinetics of praziquantel in humans, possibly through inhibition of CYP3A, particularly CYP3A4, first-pass metabolism of praziquantel. Our data suggest that when praziquantel is co-administered with ketoconazole, the dose of praziquantel could be reduced to half the standard dose of praziquantel to reduce the cost of therapy.     

Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers

This was a randomized, double-blind, placebo-controlled parallel study in human immunodeficiency virus type 1 (HIV-1)-uninfected healthy subjects to investigate the pharmacokinetic interaction between indinavir (IDV) and ritonavir (RTV). Subjects were allocated to treatment groups of IDV given with RTV in the following milligram doses twice daily: 800 mg of IDV-100 mg of RTV (800-100 mg), 800-200, 800-400, and 400-400 mg, placebo of IDV with RTV doses of 100, 200, and 400 mg, and placebo of both IDV and RTV. Doses of both drugs were administered for 14 days with a low-fat meal and one dose on day 15 with a high-fat meal. Blood was obtained for drug concentration measurements on days 14 and 15. Seventy-three volunteers enrolled in the study: 29 men and 44 women. Fifty-three volunteers completed the study. When compared to standard historical data for 800 mg of IDV every 8 h (q8h), the IDV area under the concentration-time curve for 24 h (AUC(24)) of IDV-RTV regimens 400-400, 800-100, and 800-200 mg were at least 1.4, 2.3, and 3.3 times higher, respectively, regardless of meal. The concentrations at the end of the dosing interval were 10 to 25 times higher than that observed in the standard regimen of 800 mg of IDV q8h for IDV-RTV 800-100 and 800-200 mg regimens, respectively. RTV at 200 mg maximally enhanced the IDV profile. Improved tolerability was associated with IDV-RTV 800-100 mg versus IDV-RTV 800-200, 800-400, and 400-400 mg q12h. The advantages of IDV-RTV twice daily over 800 mg of IDV q8h include no food restrictions and twice-daily dosing. Also, the regimens achieve levels of IDV that may be helpful in suppressing strains of HIV-1 that have reduced susceptibility to IDV or other protease inhibitors.     

Pharmacokinetic evaluation of guar gum-based colon-targeted drug delivery systems of mebendazole in healthy volunteers.

The pharmacokinetic evaluation of guar gum-based colon-targeted tablets of mebendazole against an immediate release tablet was carried out in human volunteers. Six healthy volunteers participated in the study and a crossover design was followed. Mebendazole was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablets. On oral administration of colon-targeted tablets, mebendazole started appearing in the plasma at 5 h, and reached the peak concentration (C(max) of 25.7+/-2.6 ng/ml) at 9.4+/-1.7 h (T(max)) whereas the immediate release tablets produced peak plasma concentration (C(max) of 37.2+/-6.8 ng/ml) at 3.4+/-0.9 h (T(max)). Colon-targeted tablets showed delayed t(max) and absorption time, and decreased C(max) and absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the guar gum-based colon-targeted tablets of mebendazole did not release the drug in stomach and small intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the drug available for local action in the colon.     

Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers

To determine the mechanism of the amiodarone-phenytoin interaction, seven healthy male subjects were given intravenous phenytoin, 5 mg/kg, before (phase I) and after (phase II) 3 weeks of oral amiodarone, 200 mg/day. Serum AUC increased from 245 +/- 37.6 to 342 +/- 87.3 mg.hr/L (p = 0.007); area under the first moment curve increased from 5666 +/- 1003 to 11,632 +/- 4198 mg.hr2/L (p = 0.008); the time-averaged total body clearance decreased from 1.57 +/- 0.3 to 1.17 +/- 0.33 L/hr (p = 0.0004); and the apparent elimination half-life increased from 16.1 +/- 1.32 to 22.6 +/- 3.8 hours (p = 0.001) for phenytoin during phase II. The volume of distribution at steady state and the unbound fraction for phenytoin remained unchanged. However, the formation of p-hydroxyphenytoin as a function of serum phenytoin concentration decreased during phase II. These findings suggest that amiodarone inhibits phenytoin metabolism. These observations also suggest that phenytoin doses will need to be reduced when coadministered with amiodarone. The magnitude of this reduction is difficult to predict because of the saturable pharmacokinetics of phenytoin, and therapeutic monitoring is recommended if amiodarone is added to the phenytoin regimen.     

Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers

The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC(ss), C(max,ss), and C(min,ss) by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUC(ss) of clarithromycin, but the median T(max,ss)for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.     

Pharmacokinetic interaction between darunavir boosted with ritonavir and omeprazole or ranitidine in human immunodeficiency virus-negative healthy volunteers

Darunavir (DRV; TMC114; Prezista) is a human immunodeficiency virus (HIV) protease inhibitor used in combination with low-dose ritonavir (RTV) (DRV/r) as a pharmacokinetic enhancer. Protease inhibitor absorption may be decreased during coadministration of drugs that limit stomach acid secretion and increase gastric pH. This study was conducted to investigate the effect of ranitidine and omeprazole on the plasma pharmacokinetics of DRV and RTV in HIV-negative healthy volunteers. Sixteen volunteers completed the study and received DRV/r, DRV/r plus ranitidine, and DRV/r plus omeprazole, in three separate sessions. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Samples were taken over a 12-h period on day 5 for the assessment of DRV and RTV plasma concentrations. Pharmacokinetic parameters assessed included DRV area under the curve, maximum plasma concentration, and trough plasma concentration. The least-squares mean ratios and 90% confidence intervals are reported with treatment of DRV/r alone as a reference. Compared with DRV/r alone, no significant changes in DRV pharmacokinetic parameters were observed during coadministration of DRV/r and either ranitidine or omeprazole. Treatment regimens were generally well tolerated, and no serious adverse events were reported. In conclusion, coadministration of DRV/r and ranitidine or omeprazole was well tolerated by the volunteers. Ranitidine and omeprazole did not have a significant influence on DRV pharmacokinetics. No dose adjustments are required when DRV/r is coadministered with omeprazole or ranitidine.     

Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers

Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (C(max)), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir C(max), AUC(0-12), and AUC(0-∞) were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs.     

Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers

OBJECTIVES: The pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers. METHODS: An unblinded, controlled, fixed-sequence, 2-period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8. Methylprednisolone and diltiazem disposition was assessed from plasma concentrations. Pharmacodynamic factors were assessed by plasma cortisol and T-helper and T-suppressor lymphocytes by means of extended indirect response models. RESULTS: The clearance of methylprednisolone was significantly reduced in the presence of diltiazem (25.2 L/h versus 16.8 L/h), resulting in a longer half-life (2.28 hours versus 3.12 hours) and increased area under the plasma concentration-time curve (AUC) (871 ng x h/mL versus 1299 ng x h/mL). The AUC of diltiazem was unchanged in the presence of methylprednisolone. No significant intrinsic pharmacodynamic differences were observed for methylprednisolone versus methylprednisolone-diltiazem. The 50% inhibitory concentration values were 0.446 ng/mL versus 0.780 ng/mL for cortisol, 9.20 ng/mL versus 10.7 ng/mL for T-helper cells, and 18.5 ng/mL versus 20.9 ng/mL for T-suppressor cells (P >.05). Greater net suppression, as indicated by the area between the effect curve and suppression ratios, was observed for the methylprednisolone-diltiazem combination versus methylprednisolone alone, which was attributed to reduced elimination of methylprednisolone. CONCLUSIONS: Controlled-delivery diltiazem, 180 mg, significantly increased methylprednisolone AUC and half-life and reduced clearance, lending to greater systemic exposure to the steroid. However, significant differences between 50% inhibitory concentration values for methylprednisolone when given alone and for methylprednisolone in combination with diltiazem were not seen, which implies no change in cortisol or cell-trafficking sensitivity in the presence of diltiazem.     

Pharmacokinetics of ceftazidime in serum and suction blister fluid during continuous and intermittent infusions in healthy volunteers.

The pharmacokinetics of ceftazidime were investigated during intermittent (II) and continuous (CI) infusion in eight healthy male volunteers in a crossover fashion. The total daily dose was 75 mg/kg of body weight per 24 h in both regimens, given in three doses of 25 mg/kg/8 h (II) or 60 mg/kg/24 h with 15 mg/kg as a loading dose (CI). After the third dose (II) and during CI, serum and blister fluid samples were taken. Seven new blisters were raised for each timed sample by a suction blister technique. Blisters took 90 min to form. Samples were then taken from four blisters (A samples) and 1 h later were taken from the remaining three (B samples). The concentration of ceftazidime was determined using a high-performance liquid chromatography method. After II, the concentrations in serum immediately after infusion (t = 30 min) and 8 h after the start of the infusion were 137.9 (standard deviation [SD], 27.5) and 4.0 (SD, 0.7) micrograms/ml, respectively. The half-life at alpha phase (t1/2 alpha) was 9.6 min (SD, 4.6), t1/2 beta was 94.8 min (SD, 5.4), area under the concentration-time curve (AUC) was 285.4 micrograms.h/ml (SD, 22.7), total body clearance was 0.115 liter/h.kg (SD, 0.022), and volume of distribution at steady state was 0.178 liter/kg (SD, 0.023). The blister fluid (A) samples showed a decline in concentration parallel to that of the concentrations in serum during the elimination phase with a ratio of 1:1. The t1/2 of the A samples was 96.4 min (SD, 3.2). The concentration of ceftazidime in the B blister fluid samples was significantly higher (27%) than in the A samples over time. This shows that blisters may behave as a separate compartment and establishes the need to raise new blisters for each timed sample. The mean AUC/h during continuous infusion was 21.3 micrograms . h/ml (SD, 3.0). The total body clearance was 0.113 liter/h . kg (SD, 0.018), the urinary clearance was 0.105 liter/h . kg (SD, 0.012), and the ceftazidime/creatinine clearance ratio was 0.885. The mean AUC of blister fluid per hour was 84.5% (18.0 micrograms . h/liter; SD, 3.6) compared with that of serum. The A samples did not differ significantly from the B samples. The implications of continuous infusion of beta-lactams for treatment of serious infections are discussed.     

Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers

Flurbiprofen is a propionic acid–derived nonsteroidal anti–inflammatory drug (NSAID) used widely in the treatment of rheumatism and nonarthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two–part, open study involving healthy adult volunteers. In the first (cross–over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen–containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen–containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high–performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (C_max) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean ± SD: 43 ± 16 ng/ml versus 5999 ± 1300 ng/ml, respectively). After repeated application of the topical patch, C_max increased only slightly to 103 ± 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3–5 ± 1–7%, calculated from plasma area under the curve data and 4-4 ± 2–8% from urinary excretion data. The temporal profile of the appearance of flurbiprofen in the circulation also differed, with maximum concentrations occurring (T_max) 2 ± 1 h after the oral dose but not until 20 ± 6 h of applying the first patch, decreasing to 4 ± 3 h after repeated applications. Steady–state plasma concentrations were reached within 5 days of repeated patch applications; these exhibited intersubject variability ranging from 32 to 285 ng/ml. Percutaneous absorption of flurbiprofen from the patch into the systemic circulation was thus relatively slow and systemic concentrations of the drug achieved by this route were much lower than those obtained after oral intake of comparable doses. The systemic concentrations achieved via the topical route are likely to be insufficient to account for the demonstrable efficacy of the formulation in clinical trials, which is considered to depend on local enhanced topical delivery of flurbiprofen. Moreover, it might reasonably be supposed that the use of the flurbiprofen–containing patch as a localized treatment for musculoskeletal soft–tissue lesions will elicit a lower incidence of systemic adverse effects than occurs with the orally administered NSAID.     

Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers

Tenofovir disoproxil fumarate (tenofovir DF) was studied in combination with rifampin in 24 healthy subjects in a multiple-dose, open-label, single-group, two-period study. All subjects were given tenofovir DF at 300 mg once a day (QD) from days 1 to 10 (period 1). From days 11 to 20 the subjects received tenofovir DF at 300 mg combined with rifampin at 600 mg QD (period 2). The multiple-dose pharmacokinetics of tenofovir (day 10 and 20) and rifampin (day 20) were assessed. The drug-related adverse events (AEs) experienced during this study were mostly mild. Only one grade 3 AE possibly or probably related to the treatment (raised liver enzyme levels) occurred during period 2; the subject was withdrawn from the study. Pharmacokinetic data for 23 subjects were thus evaluable. Point estimates for the mean ratios of tenofovir with rifampin versus tenofovir alone for the area under the concentration-time curve from time zero to 24 h (AUC(0-24)), the maximum concentration of drug in plasma (C(max)), and the minimum concentration of drug in plasma (C(min)) were 0.88, 0.84, and 0.85, respectively. The 90% classical confidence intervals for AUC(0-24), C(max), and C(min) were 0.84 to 0.92, 0.78 to 0.90, and 0.80 to 0.91, respectively, thus suggesting pharmacokinetic equivalence. Similarly, coadministration of rifampin and tenofovir DF did not result in changes in the values of the tenofovir pharmacokinetic parameters. For rifampin, the values of the pharmacokinetic parameters found in this study were comparable to those found in the literature, indicating that tenofovir DF has no effect on the pharmacokinetics of rifampin. In conclusion, adaptation of either the rifampin or the tenofovir DF dose for the simultaneous treatment of tuberculosis and human immunodeficiency virus (HIV) infection in HIV-infected patients is probably not required.