Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler.

The propellant-free Combivent Respimat Soft Mist Inhaler (CVT-R) was developed to replace the chlorofluorocarbon-propelled Combivent metered-dose inhaler (CVT-MDI). This steady-state pharmacokinetic (PK) substudy evaluated drug lung-delivery efficiency, using data from two phase III safety and efficacy trials. PK parameters were obtained from well-controlled population PK analyses. Area under the plasma concentration-time curve (AUC), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) showed systemic exposure to ipratropium bromide and albuterol delivered via the CVT-R was proportional to ex-mouthpiece delivered dose. Although the labeled dose of ipratropium bromide in the CVT-R was half that in the CVT-MDI, the systemic exposure was comparable. No PK interaction for the ipratropium bromide and albuterol Respimat drug components was demonstrated. Ipratropium bromide alone resulted in similar exposure to the combination of ipratropium bromide and albuterol. These results show that CVT-R delivers drug more efficiently to the lung than CVT-MDI.

Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: BILR 355 is a second generation non-nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti-HIV-1 activities and favourable human pharmacokinetic properties after co-administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter-mediated pathway. These two drugs are likely to be given together to HIV-infected patients. The objective of this study was to investigate any steady-state pharmacokinetic interactions between RTV-boosted BILR 355 and 3TC/zidovudine (ZDV). METHODS: This was a randomized, open label, prospective study. In group A, 39 healthy subjects were given 3TC/ZDV (150 mg/300 mg) twice daily (b.i.d.) for 7 days, and then BILR 355 and RTV (BILR 355/r, 150 mg/100 mg) were co-administered with this regimen for an additional 7 days. Intensive blood samples were taken on days 7 and 14 for pharmacokinetic assessments. In group B, 12 healthy subjects were given BILR 355/r (150 mg/100 mg) b.i.d. for 7 days. The pharmacokinetic data from group B were pooled with data from group B subjects in other similar studies performed in parallel (BILR 355 alone group in BILR 355 drug-drug interaction studies with tipranavir, lopinavir/RTV, and emtricitabine/tenofovir DF; BILR 355 regimen was the same). RESULTS AND DISCUSSION: After co-administration with BILR 355/r, the AUC(12,ss) and C(max,ss) of 3TC increased by 45% and 24%, respectively; the elimination half-life (t(1/2) ,ss) of 3TC was significantly increased. However, the pharmacokinetics of ZDV was unchanged. Co-administration with 3TC/ZDV resulted in a 22% decrease in AUC(12,ss) and a 20% decrease in C(max,ss) for BILR 355. The observed increase in exposure and prolongation of t(1/2,ss) of 3TC is potentially related to inhibition of OCT-mediated urinary excretion of 3TC. WHAT IS NEW AND CONCLUSION: Concomitant administration of BILR 355 with 3TC/ZDV resulted in a modest decrease in exposure to BILR 355 and a 45% increase in exposure to 3TC.

Effect of tipranavir/ritonavir combination on the pharmacokinetics of tadalafil in healthy volunteers.

This study evaluated the effects of single-dose administration and steady-state concentrations of tipranavir 500 mg and ritonavir 200 mg (TPV/r) combination on the pharmacokinetics of tadalafil 10 mg (TAD) in an open-label study. Seventeen healthy male volunteers received sequential dosing of the studied product: TAD (day 1) alone in a single dose for 7 days followed by TAD (day 8) in a single dose with TPV/r (500/200 mg twice daily, days 8-18). Pharmacokinetic parameters were determined in a noncompartmental analysis. The geometric mean ratio and 90% confidence interval were used to evaluate drug interactions. The effect of a single dose of TAD on the pharmacokinetics of TPV/r resulted in a small decrease in exposure after either first-dose or steady-state TPV/r (geometric mean ratios [90% confidence interval]: area under the concentration-time curve, 0.85 [0.74-0.97]). In contrast, coadministration of TAD exposure was increased significantly (2.33 [2.02-2.69]) when administered with the first dose of TPV/r but not when TPV/r steady state was reached (1.01 [0.83-1.21]). Antiretroviral activity may not be reduced, but the dose of TAD should be reduced at the start of TPV/r therapy and then a full dose can be resumed after steady state is reached.

A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.

Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection.

The purpose of this parallel treatment group, double-blind, multicenter study was to characterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts < 200 cells/mm3and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddI], zalcitabine [ddC], stavudine [d4T]) therapy were randomly assigned to be treated with either nucleoside + lamivudine + nevirapine or nucleoside + lamivudine + placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddI, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F = 3.3 L/hour; 95% confidence interval [CI] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% CI 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers.

The results of two randomized, single-dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short-term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean +/- S.D., Cl = 1.4 +/- 0.3 L/h) and a prolonged elimination phase (t(1/2beta) = 52.8 +/- 14.8 h; MRT = 81.4 +/- 22.4 h). Nevirapine absolute bioavailability was 93 +/- 9% and 91 +/- 8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production-line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose.

In vitro protein binding behavior of dipyridamole.

The in vitro protein binding behavior of dipyridamole in plasma and buffered protein solutions was investigated by equilibrium dialysis. The drug was highly protein bound (approximately 98%) in heparinized human plasma, and the extent of protein binding remained constant for drug concentrations over the range of therapeutic interest of 0.1-10 micrograms/mL. Comparable binding results were obtained with a mixture of 80 mg % of alpha 1-acid glycoprotein and 40 g/L of human serum albumin in pH 7.4 phosphate buffer solution. Pure alpha 1-acid glycoprotein (80-400 mg %) or pure human serum albumin (40 g/L) in phosphate buffer gave significantly (p less than 0.05) lower binding results, indicating that both proteins are responsible for the high binding of dipyridamole in plasma. Addition of alpha 1-acid glycoprotein to heparinized human plasma, to simulate an acute phase increase in the protein, had no effect on the fraction of free drug in plasma. Binding of dipyridamole to heparinized human plasma or human serum albumin in buffer was concentration independent through 40 micrograms/mL. The free fraction of dipyridamole increases with concentrations exceeding 40 micrograms/mL.

Efficacy of oral mexiletine therapy at a 12-h dosage interval.

The antiarrhythmic effectiveness and safety of 12-h oral administration of mexiletine were evaluated in adult outpatients with a baseline hourly rate of PVCs of 30 or higher who had initially shown at least a 50 percent reduction of this rate when treated with mexiletine at an 8-h dosage interval. Doses were titrated on the basis of 24-h Holter monitoring for both 8- and 12-h intervals. Seventeen of 26 patients showed PVC reductions after 8-h treatment. Fifteen of these 17 patients reached the goal reduction of greater than or equal to 50 percent in the hourly PCV rate with 12-h dosing. Hour-by-hour analysis disclosed a consistent degree of PVC suppression throughout both 8- and 12-h dose intervals. No increase in the incidence of adverse effects was associated with conversion to the 12-h regimen.

Clinical pharmacokinetics of clonidine.

Clonidine is a centrally active antihypertensive agent effective in the treatment of mild, moderate and severe hypertension, alone or in combination with other drugs. Use of oral clonidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal clonidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory, transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix, a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin, and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the clonidine transdermal system to both normotensive and hypertensive subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application, and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine, the amount of clonidine released being proportional to its surface area. Thus, the daily dose is regulated by the area of skin covered. Typically, steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason, it is recommended that dosages be titrated up from the smallest system (3.5 cm2) until the desired pharmacological effect has been obtained.(ABSTRACT TRUNCATED AT 400 WORDS)

Relative bioavailability of chlorthalidone in humans after single oral doses.

The relative bioavailability of chlorthalidone from rapidly dissolving, stabilized, amorphous 15- and 25-mg formulations was compared in 24 normal adult male volunteers to the 25-mg market standard tablet and a 25-mg oral reference solution. When adjusted for dose, the experimental formulations were 116 and 104% of the calculated mean area under the curve for chlorthalidone reference solution compared to 81% for the tablet of the innovator. Likewise, the dose-adjusted mean peak blood levels for the 15- and 25-mg experimental tablets and the 25-mg tablet of the innovator were 112, 105 and 78% of the reference solution, respectively. Mean times-to-peak blood concentrations were 8.4 h for the 25-mg and 9.1 h for the 15-mg amorphous formulations compared to 9.2 h for the oral reference solution and 11.8 h for the market standard tablet. Drug concentrations declined monoexponentially with harmonic mean half-lives ranging from 47 to 55 h and intrinsic clearances ranging from 0.13 to 0.18 L/h regardless of formulation. The dose-adjusted relative bioavailability for the experimental formulations was not significantly different from the oral reference solution, whereas the market standard tablet was significantly (p less than 0.0001) lower than the reference solution. The urinary excretion of chlorthalidone was generally greater following the stabilized amorphous formulations than either the tablet of the innovator or the reference solution. The results of this research show that a rapidly dissolving chlorthalidone tablet can be formulated that shows complete relative bioavailability in humans.

Pharmacokinetics of transdermally delivered clonidine.

We detail a series of pharmacokinetic investigations to determine the dose linearity, the effect of site of application, the duration of steady-state plasma concentrations, and the effect of chronic application when clonidine is administered transdermally. Dose linearity was assessed in six subjects with normotension after application of increasing sizes of transdermal clonidine systems (3.5, 7.0, and 10.5 cm2 size) to the upper outer arm. Of the six subjects studied, five had linear relationships between clonidine plasma concentrations at steady state and system size of greater than 0.975; in the sixth subject the correlation was greater than 0.90. The mean steady-state plasma concentrations with 3.5, 7.0, and 10.5 cm2 systems were 0.39, 0.84, and 1.12 ng/ml, respectively. The influence of site and duration of application on the absorption of transdermal clonidine was studied in eight subjects with normotension by use of the 3.5 cm2 system. The mean steady-state plasma concentration over the time interval from 3 to 7 days after application to the arm or to the chest did not significantly differ. When a system was left on the chest or arm for a total of 11 days (4 days beyond the recommended time to change systems), the plasma concentrations of seven of eight subjects with application to the arm and of six of eight subjects with application to the chest remained constant through day 11. The influence of consecutive applications of 3.5 cm2 transdermal clonidine systems on steady-state plasma clonidine concentrations was also studied in eight subjects with normotension over an 11-day period.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorthalidone pharmacodynamics in beagle dogs.

A pharmacodynamic approach was employed to examine the diuretic effect of chlorthalidone in beagle dogs and to identify parameters necessary for optimization of an oral dosage formulation of this drug. The extensive partitioning of chlorthalidone into erythrocytes was shown to be noninstantaneous, with an in vitro partitioning half-life of 18 min. In vivo studies using oral and intravenous solutions confirmed this finding. Additionally, the diuretic effect was demonstrated to be related to the drug concentration in the plasma fraction. These studies led to the development of a relevant pharmacokinetic model which highlighted the importance of the oral absorption rate on the diuretic efficacy of chlorthalidone. A novel, rapidly dissolving, stabilized, amorphous chlorthalidone tablet formulation was compared to various oral solution and tablet formulations. Pharmacokinetic analysis by classical compartmental models and by moment techniques demonstrated that the rapidly dissolving tablet formulation was bioequivalent to an oral solution of chlorthalidone. Preparations containing crystalline chlorthalidone are shown to be incompletely absorbed, and the rates of absorption favor partitioning into the erythrocyte fraction. It is projected from the pharmacodynamic model that the novel chlorthalidone preparation optimizes plasma levels necessary to invoke a diuretic response.

Pharmacokinetics of oral sustained release clonidine in humans.

Tablet cores of clonidine (Catapres) showing varying rates of in vitro dissolution were administered in a crossover study with intravenous clonidine to determine the rate of absorption into the systemic circulation in humans. Excellent bioavailability (0.87-0.96) was obtained in all 12 subjects for each of the formulations. When peak concentration and time to peak are compared for the standard immediate release cores and the cores designed to be slowly dissolving there was a significant difference (p less than 0.05). Absorption rate plots for each formulation in each subject were obtained using the Loo-Riegelman procedure of comparing the oral pharmacokinetic profile with the intravenous profile. As the release from the cores were formulated to be slower, the in vivo absorption rate of clonidine approached zero order input. Incorporating combinations of sustained release and immediate release cores into a capsule (Perlonget) gave predictable absorption rates, permitting the formulation scientist to control the plasma levels obtained from oral dosing of clonidine. The intravenous pharmacokinetics of clonidine after a 0.2 mg infusion followed a tri-exponential decline with a final phase half-life of 13.6 h (harmonic mean). Following the intravenous infusion 42.3% of the dose was excreted unchanged in the urine with a renal clearance of 10.05 +/- 0.65 1/h (167 ml/min).

Analysis of chlorthalidone in biological fluids by high-performance liquid chromatography using a rapid column cleanup procedure.

A high-performance liquid chromatographic assay usable for clinical monitoring of chlorthalidone in biological fluids was developed. Extraction efficiency was greater than 80% for blood and urine using a rapid, disposable column cleanup procedure. Chlorthalidone could be reliably measured in the range of 100-4,000 ng/ml in biological fluids with excellent day-to-day reproducibility and within-day precision. Chlorthalidone was found to be stable at -20 degrees C in blood and urine for at least 1 year, permitting repeat assays and large clinical studies to be conducted. The pharmacokinetics of chlorthalidone was studied in 24 subjects over a 120-h time interval following a single dose. chlorthalidone has a long terminal half-life in whole blood of 49 h, with peak concentrations occurring 8-10 h after oral dosing. During the first 12 h after dosing, chlorthalidone was rapidly excreted into urine followed by a slower phase with a half-life of 49 h.

Isolation and characterization of metaproterenol-3-O-sulfate: a conjugate of metaproterenol in human urine.

Metaproterenol (1-(3,5-dihydroxyphenyl)-2-isopropylaminoethanol) is primarily converted in humans to metaproterenol-3-O-sulfate following oral administration. Ion exchange column chromatography with a gradient of ammonium acetate buffer permitted the isolation of the ammonium salt of metaproterenol-3-O-sulfate from human urine. Treatment of aliquots of the column eluate with purified sulfatase and subsequent HPLC/fluorescence analysis confirmed the presence of metaproterenol. Comparison of the column eluate with a metaproterenol standard by 250-MHz proton-NMR revealed a pattern consistent with monosubstitution of the resorcinol ring. Negative and positive ion fast atom bombardment/mass spectrometry showed the metabolite to have a (M-H)- m/z of 290 and a (M + H)+ m/z ion of 292. These three methods support the structural assignment of metaproterenol-3-O-sulfate. Enzymatic hydrolysis of urine specimens from 29 different subjects with purified beta-glucuronidase as well as beta-glucuronidase-sulfatase mixtures yielded no significant increase in metaproterenol beyond purified sulfatase-treated urine, thus ruling out the presence of a glucuronide of metaproterenol. Approximately 40% of an oral 20-mg dose, given as either a tablet or a solution, was recovered in the urine as metaproterenol-3-O-sulfate. Approximately 5% of the dose was recovered in the unconjugated form. The majority of the dose was excreted over the first 12 hr with a biological half-life of 5-6 hr followed by a slower excretion phase with a half-life of 20 hr.

Naltrexone metabolism and sustained release following administration of an insoluble complex to rhesus monkeys and guinea-pigs.

Both the release and the metabolism of naltrexone have been evaluated after intramuscular administration of a sustained release [15,16-3H2]naltrexone aluminium tannate complex in guinea-pigs and rhesus monkeys. In both species, measurable excretion of radioactivity was obtained for greater than 50 days and complete recovery of the dose was obtained in the guinea-pig. The radioactivity excretion rate-time profile differed in the two species with guinea-pig yielding a continuously declining rate and monkey yielding a peak at 5 days. In selected monkey urine samples (days 4, 17-20 and 49-52) subjected to t.l.c., evidence was obtained for the presence of naltrexone, beta-naltrexol and 2-hydroxy-3-O-methyl-beta-naltrexol, mostly as glucuronide and/or sulphate conjugates. The t.l.c. data also suggest that in monkey a naltrexone metabolite builds up relative to naltrexone over the 52 day release period.