Lack of pantoprazole drug interactions in man: an updated review.

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Various mechanisms have to be considered as causes for potential drug-drug interactions. Proton pump inhibitors (PPIs) in general may alter the absorption of drugs by increasing the intragastric pH. Due to the presence of an imidazole ring, the PPIs of the class of substituted benzimidazole sulfoxides may interfere with the metabolism of other drugs by altering the activity of drug metabolizing enzymes of the cytochrome P450 system, via either induction or inhibition. With the increasing use of PPIs, their interaction potential gains therapeutic importance as was the case with the first and second generation of H2-blockers (cimetidine and ranitidine, respectively). The enhanced selectivity of pantoprazole to the gastric H+/K(+)-ATPase characterizes the new PPI generation. In contrast to omeprazole, pantoprazole has a low potential to interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, substrates for all relevant cytochrome P450 families involved in the metabolism of drugs in man were investigated. Pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, a hormonal contraceptive (combination of levonorgestrel and ethinylestradiol), metoprolol, nifedipine, phenprocoumon, phenytoin, theophylline and warfarin in man. Pantoprazole also neither induced the metabolism of antipyrine or caffeine, nor increased urinary excretion of the induction markers D-glucaric acid and 6 beta-hydroxycortisol. Vice versa, the investigated drugs had no relevant influence on the pharmacokinetics of pantoprazole.

Pharmacokinetics and drug interactions--relevant factors for the choice of a drug.

Pharmacokinetics serve as a useful tool in drug development by identifying the drug's disposition and elimination characteristics, the absorption characteristics of the biopharmaceutical formulation, and the therapeutic dose regimen in various patient populations. Where two or more drugs of a class have a similar efficacy, the choice of the drug may depend upon the reproducibility of the pharmacokinetics and the minimal risk of drug interaction. Pantoprazole, a selective proton pump inhibitor, appears to meet the above criteria. As opposed to other members of the class, pantoprazole exhibits linear, predictable pharmacokinetics and lack of drug interactions.

Lack of pharmacokinetic interaction as an equivalence problem.

The demonstration that concomitant administration of drug B does not affect the pharmacokinetics of drug A can be adequately handled as an equivalence problem. Administration of drug A alone serves as reference and simultaneous administration of drugs A and B as test situation. The range of clinically acceptable variation in the pharmacokinetic characteristics of drug A defines the equivalence range. This will usually correspond to the bioequivalence range accepted for the comparison of different formulations of drug A. Equivalence, i.e. lack of pharmacokinetic interaction, is concluded if the 90%-confidence interval for the ratio (difference) of the expected medians for test and reference is entirely within the equivalence range. This decision procedure ensures that the consumer risk of incorrectly concluding "lack of interaction" is limited to 5%. Moreover, the producer risk of incorrectly concluding "interaction" can be controlled by appropriate sample sizes.

Lack of pantoprazole drug interactions in man: an updated review.

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Various mechanisms have to be considered as causes for potential drug-drug interactions. Proton pump inhibitors (PPIs) in general may alter the absorption of drugs by increasing the intragastric pH. Due to the presence of an imidazole ring, the PPIs of the class of substituted benzimidazole sulfoxides may interfere with the metabolism of other drugs by altering the activity of drug metabolizing enzymes of the cytochrome P450 system, via either induction or inhibition. With the increasing use of PPIs, their interaction potential gains therapeutic importance as was the case with the first and second generation of H2-blockers (cimetidine and ranitidine, respectively). The enhanced selectivity of pantoprazole to the gastric H+/K(+)-ATPase characterizes the new PPI generation. In contrast to omeprazole, pantoprazole has a low potential to interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, substrates for all relevant cytochrome P450 families involved in the metabolism of drugs in man were investigated. Pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, a hormonal contraceptive (combination of levonorgestrel and ethinylestradiol), metoprolol, nifedipine, phenprocoumon, phenytoin, theophylline and warfarin in man. Pantoprazole also neither induced the metabolism of antipyrine or caffeine, nor increased urinary excretion of the induction markers D-glucaric acid and 6 beta-hydroxycortisol. Vice versa, the investigated drugs had no relevant influence on the pharmacokinetics of pantoprazole.

Lack of pantoprazole drug interactions in man.

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Different mechanisms have to be considered as causes for potential drug-drug interactions. Proton pump inhibitors (PPIs) in general may alter the absorption of drugs by increasing the intragastric pH. Due to the presence of an imidazole ring, the PPIs of the class of substituted benzimidazole sulfoxides may interfere with the metabolism of other drugs by altering the activity of drug metabolizing enzymes of the cytochrome P450 system, via either induction or inhibition. With the increasing use of PPIs, their interaction potential gains therapeutic importance as was the case with the first and second generation of H2-blockers (cimetidine and ranitidine, respectively). The enhanced selectivity of pantoprazole to the gastric H+/K(+)-ATPase characterizes the new PPI generation. In comparison to omeprazole and lansoprazole, pantoprazole showed a much lower affinity to cytochrome P450 in vitro and a markedly lower potency in the in vivo rat model for interaction with diazepam. In contrast to omeprazole, pantoprazole does not interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, diazepam, digoxin, a hormonal contraceptive, nifedipine, phenytoin, theophylline and warfarin in man. Also pantoprazole neither induced the drug metabolism of antipyrine nor increased urinary excretion of the induction markers D-glucaric acid and 6 beta-hydroxycortisol. Vice versa, the investigated drugs had no relevant influence on the pharmacokinetics of pantoprazole.

Lack of pharmacokinetic interaction as an equivalence problem.

The demonstration that concomitant administration of drug B does not affect the pharmacokinetics of drug A can be adequately handled as an equivalence problem. Administration of drug A alone serves as reference and simultaneous administration of drugs A and B as test situation. The range of clinically acceptable variation in the pharmacokinetic characteristics of drug A defines the equivalence range. This will usually correspond to the bioequivalence range accepted for the comparison of different formulations of drug A. Equivalence, i.e. lack of pharmacokinetic interaction, is concluded if the 90%-confidence interval for the ratio (difference) of the expected medians for test and reference is entirely within the equivalence range. This decision procedure ensures that the consumer risk of incorrectly concluding "lack of interaction" is limited to 5%. Moreover, the producer risk of incorrectly concluding "interaction" can be controlled by appropriate sample sizes.

Lack of pharmacokinetic interaction as an equivalence problem.

The demonstration that concomitant administration of drug B does not affect the pharmacokinetics of drug A can be adequately handled as an equivalence problem. Administration of drug A alone serves as reference and simultaneous administration of drugs A and B as test situation. The range of clinically acceptable variation in the pharmacokinetic characteristics of drug A defines the equivalence range. This will usually correspond to the bioequivalence range accepted for the comparison of different formulations of drug A. Equivalence, i.e. lack of pharmacokinetic interaction, is concluded if the 90%-confidence interval for the ratio (difference) of the expected medians for test and reference is entirely within the equivalence range. This decision procedure ensures that the consumer risk of incorrectly concluding "lack of interaction" is limited to 5%. Moreover, the producer risk of incorrectly concluding "interaction" can be controlled by appropriate sample sizes.

Lipid lowering treatment with bezafibrate in patients on chronic haemodialysis: pharmacokinetics and effects.

Hyperlipidaemia may contribute to the high rate of cardiovascular complications in patients on chronic haemodialysis (CHD). However, possibilities of lipid lowering therapy in CHD are still limited. The applicability of bezafibrate (BF), a recently developed clofibrate analogue, was investigated in patients on CHD with triglyceride and/or total cholesterol levels above 300 mg/dl. The lipid lowering effect was studied in a placebo-controlled trial over 6 months in 19 patients. Long-term effect was followed in six patients over a mean period of 29 months. Elimination half-life and mean therapeutic serum concentration were calculated by 72-h BF serum profiles, obtained after the first drug administration of a single 200-mg dose and during steady state after 12 weeks of treatment. Elimination half-lives were 17 h at start and 22 h after 12 weeks compared with 2 h in subjects with normal renal function. Dose reduction to 200 mg every 3rd day was necessary and resulted in a mean therapeutic serum concentration of 3.4 mg/l, which was similar to 3.0 mg/l of normal subjects, who received the dose optimal for lowering of lipids (200 mg 3 X/day). The protein-bound serum fraction of BF was decreased to 8% in CHD patients, compared with 95% found in normal subjects. BF therapy resulted in a marked reduction of serum triglycerides from 478 mg/dl by 31% and total cholesterol levels from 311 mg/dl by 19% as well as beta-Lp-cholesterol from 178 mg/dl by 17%, whereas the initially low alpha-Lp-cholesterol increased significantly from 18.3 mg/dl by 58%.(ABSTRACT TRUNCATED AT 250 WORDS)

[The pharmacokinetics and bioavailability of urapidil. In vitro/in vivo correlations of different experimental formulations]. / Zur Pharmakokinetik und Bioverfügbarkeit von Urapidil. In-vitro-/in-vivo-Korrelation verschiedener experimenteller Zubereitungen.

The pharmacokinetic parameters, including the relative bioavailabilities of two experimental batches of a 60-mg urapidil slow release-capsule and a 30-mg urapidil drinking ampoule (Ebrantil) had to be evaluated in a randomized, three-period change-over study with 12 healthy volunteers after single dosing. The appropriate parameters for the capsule formulations were compared with their dissolution rates obtained by different in vitro models. The capsules showed different half-change, but comparable single-fluid dissolution profiles. Both batches of the capsules showed equivalence with respect to the extent of absorption, in connection with 100% relative bioavailability on average. A correlation of the in vivo parameters Tmax and Cmax with the half-change model can be assumed.

Once daily theophylline: multiple-dose comparison of an encapsulated micro-osmotic system (Euphylong) with a tablet (Uniphyllin).

In a randomized, multiple-dose, cross-over study, serum theophylline concentrations (STC) were compared in 12 healthy volunteers for 24 hours after the first and seventh administration of two sustained-release formulations. The preparations tested were the new encapsulated micro-osmotic system Euphylong (E) and the tablet Uniphyllin (U). Daily doses of 800 mg were administered at 7 p.m., half an hour after a standardized evening meal. The relative bioavailability of E with respect to U under steady-state conditions is 93 (83-105)%. In contrast to U, E markedly truncates the high peak concentrations and leads to a sustained, plateau-like concentration throughout the night. Therefore prediction of individual maximum serum levels becomes possible for E on the basis of one blood sample taken in the morning. The significantly improved in vivo performance of E in comparison with U is reflected in a 50% reduction of the swing, a 60% increase in the plateau time, and a substantial reduction of theophylline-specific side effects such as nausea, palpitations and increased diuresis.

Pharmacodynamics and pharmacokinetics of three different doses of urapidil infused in hypertensive patients.

The study was designed to follow the haemodynamic effects and pharmacokinetics under steady-state conditions of three different doses of urapidil infused continuously. Nine male hypertensive patients received three randomly assigned intravenous infusions of 32.5, 65 and 130 mg urapidil, over 14 h during 6 consecutive days, in a change-over fashion. Blood pressure and heart rate were measured over a period of 28 h after the infusion began and were compared with a reference profile obtained prior to the treatment periods. Urapidil and its main metabolite, parahydroxylated urapidil, were also determined for 28 h after the infusion began using HPLC. The 32.5 mg dose of urapidil caused a maximum decrease in systolic blood pressure of 33 +/- 8 mmHg, the 65 mg dose a maximum decrease of 39 +/- mmHg and the 130 mg dose a maximum decrease of 50 +/- 12 mmHg. The 32.5 and 65 mg doses resulted in similar serum urapidil concentrations, with maximum levels in the 100 to 200 ng/ml range, and the 130 mg dose caused a maximum level approximately four times that achieved with the 32.5 mg dose. The serum concentration of parahydroxy urapidil was proportional to the corresponding dose of urapidil. Four patients reported mild headache, fatigue, weakness, pressure in the head, perspiration and orthostatic dysregulation. The side-effects were probably drug related but required no specific therapy. In summary, the 32.5 mg dose of urapidil resulted in a pronounced decrease in blood pressure. The average pressure reduction over the 14-h infusion period showed further dose-dependent increases after the 65 and 130 mg doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Deficient feedback regulation of erythropoiesis in kidney transplant patients with polycythemia.

Anemia of endstage renal failure improves shortly after kidney transplantation. However, in about 10% of transplanted patients polycythemia occurs. By use of a sensitive in vitro bioassay the pathogenetic role of erythropoietin (Ep) was investigated in 12 patients with post-transplant erythrocytosis (PTE), and compared to 12 non-PTE patients. The mean Ep of 160 mU/ml was significantly elevated in patients with PTE as compared to 25 mU/ml of 36 healthy controls, whereas, the mean Ep of 24 mU/ml in non-PTE patients did not differ significantly from healthy controls. To further elucidate the mechanism of inappropriate Ep production, selective venous catheterization of native and transplanted kidneys was performed in six patients. In four PTE patients the mean Ep in native kidney veins of 110 mU/ml was significantly higher than the peripheral Ep of 66 mU/ml, whereas, mean Ep in kidney graft veins was 51 mU/ml. In contrast, in two non-PTE patients no significant difference between mean Ep from native and transplanted kidney veins was observed. We conclude that some patients escape from normal feedback regulation either due to autonomous Ep production or due to feedback regulation at an elevated level of hematocrit and that inappropriate Ep production originates from the diseased native kidneys.

Effect of secondary hyperparathyroidism on the anaemia of end-stage renal failure: in vivo and in vitro studies.

Changes in haematocrit of 29 haemodialysis patients were followed 12 months before, close to and 12 months after parathyroidectomy. Mean haematocrit decreased significantly from 31.6 +/- 8.6 per cent to 29.1 +/- 8.4 per cent and increased to 33.3 +/- 7.9 per cent after PTX. Serum erythropoietin concentration, investigated pre and 6-12 months post PTX, at a time, when an increase of haematocrit values had been observed, did not significantly change (63 +/- 58 vs 67 +/- 37 mU/ml). The effect of 1-84 bovine parathyroid hormone on erythropoiesis was studied in vitro. A dose-related inhibition of colony formation of both fetal mouse liver and human bone marrow erythroid cells was observed in the presence of two to 8U parathyroid hormone/ml, suggesting direct bone marrow toxicity by excessive parathyroid hormone concentrations.

Identification of spermine as an inhibitor of erythropoiesis in patients with chronic renal failure.

Fetal mouse liver and normal human bone marrow cell cultures were used for studies on the inhibition of erythroid colony formation (CFU-E) by sera from anemic patients with end-stage renal failure and the polyamine spermine. Sera from each of eight predialysis uremic anemic patients with end-stage renal failure produced a significant (P < 0.001) inhibition of erythroid colony formation in the fetal mouse liver cell cultures when compared to sera from normal human volunteers. In vivo or in vitro dialysis of the uremic sera with a 3,500-dalton exclusion limit membrane removed the inhibitor from uremic sera. The uremic serum dialysate provided by the membrane fractionation was significantly inhibitory in the erythroid cell cultures. When this dialysate was applied to gel filtration chromatography (Bio-Gel P-2) the inhibitor was found to be in the same molecular weight range as [(14)C]spermine. The polyamine spermine produced a dose-related inhibition of erythroid colony formation (CFU-E) in fetal mouse liver and normal human bone marrow cultures. Thus, the following evidence is provided that the in vitro inhibitor of erythropoiesis found in chronic renal failure patients' sera is identical with the polyamine spermine: (a) the inhibitor and radiolabeled spermine appeared in identical Bio-Gel P-2 effluent fractions; (b) when spermine was added to normal human sera at concentrations reported in sera of uremic patients, and studied in both the fetal mouse liver cell culture and normal human bone marrow cultures, a dose-related inhibition of erythroid colony (CFU-E) formation was noted; and (c) the inhibitory effects of crude uremic serum, uremic serum dialysate, and fractions of uremic serum dialysate from a Bio-Gel column, on erythroid colony formation were completely abolished by the addition of a specific rabbit antiserum to spermine.

Albuterol-induced erythropoietin production and prostaglandins release in the isolated perfused dog kidney.

The present study was designed to attempt to clarify the mechanism by which the specific beta-2 adrenergic agonist albuterol causes an enhancement of erythropoietin (Ep) production in the isolated perfused dog kidney. We have postulated previously that prostaglandins (PG) release is an early event in initiating a cascade which leads to enhanced kidney production of Ep. In the present study, the posthypoxic dog kidney was perfused for 5 hr with blood containing 500 microgram/l of albuterol. A significant (P<.001) increase in prostaglandin E (PGE) concentration was seen as early as 1 hr and continued to rise over the 5-hr perfusion period. This microgram increase in PGE was correlated with a significant (P<.05) increase in Ep titers in the perfusates after 3 and 5 hr perfusion. The addition of the PG cyclooxygenase inhibitor meclofenamate (1000 micrograms/l) to the perfusate together with albuterol completely abolished the albuterol-induced increase in PGE and Ep generation in the isolated perfused kidney. No significant increase in PGE or Ep titers in the perfusates occurred during the 5-hr perfusion period in the saline and albuterol plus meclofenamate perfused groups. These data suggest that beta-2 adrenergic activation of Ep production is correlated with an increase in PGE production by the kidney which may be related to the mechanism by which beta-2 agonists enhance kidney production of Ep.

Improving anemia by hemodialysis: effect of serum erythropoietin.

Serum erythropoietin (SEP) concentration was measured on two occasions in 42 patients with terminal renal failure (1) immediately before the first hemodialysis, and (2) 3 to 27 months following the onset of regular hemodialysis treatment. Although the hematocrit (Hct) showed an increase in every patient, the SEP concentration decreased in every patient. The mean Hct rose frm 21.7 to 28.6% (volume per volume) P < 0.001), and the SEP dropped from 509 to 182 mU/ml (P < 0.001). This shows that anemia improvement is not a consequence of increased erythropoietin production but that it is most likely due to elimination of an inhibitor of the bone marrow by hemodialysis treatment. The decrease of SEP concentration has to be interpreted as a response to the improved tissue oxygenation that correlates with the hjigher hematocrit or as a consequence of further reduction of renal mass with progress of the renal disease.

Prostaglandins activation of erythropoietin production and erythroid progenitor cells.

A model is presented postulating a role for prostaglandins E and prostacyclin in kidney generation of erythropoietin and the activation of the erythroid progenitor cell (CFU-E) compartment by erythropoietin (Ep). Several criteria have been met to prove that prostanoids mediate erythropoiesis: 1) several E-type prostaglandins (PGE2, 15-methyl prostaglandin E2, 16,16-dimethyl E2, 6-keto-E1 and PGE1) produced a significant increase in radioiron incorporation in red cells of exhypoxic polycythemic mice; 2) prostaglandin E2 increased kidney production of erythropoietin in the isolated perfused dog kidney; 3) arachidonic acid, a precursor for all bisenoic prostaglandins, increased kidney production of erythropoietin in the isolated perfused dog kidney which was blocked by pretreatment with the cyclo-oxygenase inhibitor drug indomethacin; 4) hypoxemic perfusion of the isolated perfused dog kidney increased kidney production of erythropoietin and produced an elevation in prostacyclin in the perfusates; 5) albuterol, a beta-2 adrenergic agonist, produced a significant increase in perfusate levels of erythropoietin and PGE in the isolated perfused dog kidney; 6) renal ischemia increased Ep and PGE levels in renal venous plasma which was blocked by pretreatment with indomethacin; 7) prostaglandin E2 and arachidonic acid produced a significant increase in erythroid colonies (CFU-E) in vitro in normal mouse bone marrow; 8) E-type prostaglandins (15-methyl E2) increased in vivo erythroid colony (CFU-E) formation in bone marrows of post-hypoxic polycythemic mice; and 9) injections of 15-methyl E2 daily for six weeks in normal and hypoxic mice produced a significant elevation in the total circulating red cell mass. These studies indicate that hypoxic stimulation of kidney production of erythropoietin may be related to the generation of prostacyclin (PGI2). On the other hand, albuterol and ischemic (reduction in renal blood flow) stimulation of kidney production of erythropoietin involves prostaglandins of the E type. In addition, E-type prostaglandins were found to enhance the effects of erythropoietin in activating erythroid progenitor cells (CFU-E) in the bone marrow. We postulate from our model that prostaglandins E and prostacyclins are involved in the mechanism of kidney production of erythropoietin as well as the activation of the Ep-responsive cell (ERC) compartment.

Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function.

By use of the fetal mouse liver cell assay, serum erythropoietin (SEp) concentration was measured in 135 patients at various stages of chronic renal failure and in 59 healthy subjects. In patients with creatinine clearances (CCr) ranging from 2 to 40 ml/min/1.73 sq m, endocrine renal function was found to deteriorate in parallel to excretory renal function. The known negative correlation between SEp and hematocrit (Hct) was not apparent, probably because of the loss of renal mass accompanying progress of anemia and renal insufficiency. In contrast, in patients with minimal variation of residual excretory renal function, as in individual patients investigated repeatedly within a short period of time, changes of Hct were always accompanied by opposite changes of corresponding SEp concentrations. Thus, patients with chronic renal failure have a sustained regulatory feedback mechanism between Hct and SEp, which probably works at a lower level.

[Role of erythropoietin deficiency in the pathogenesis of renal anemia]. / Die Rolle des Erythropoietinmangels in der Pathogenese der renalen Anämie.

A review is given of clinical studies performed by use of a highly sensitive in-vitro erythropoietin assay (fetal mouse livercell culture) in large patients' populations to clarify the controversial role of erythropoietin deficiency in the pathogenesis of renal anemia. Studies involved a.) patients with chronic renal disease and varying degree of renal insufficiency in the predialysis phase b.) non-nephrectomized and anephric patients on regular hemodialysis treatment. The data available demonstrate that the initial phase of renal anemia is accompanied by a compensatory increase of serumerythropoietin concentration and therefore erythropoietin deficiency has to be excluded as a primary cause of the anemia of renal failure; merely a relative lack of erythropoietin seems to exist. In the terminal phase of renal failure, erythropoietin deficiency becomes absolute, such in 50% of the investigated non-nephrectomized hemodialysis patients and in all anephric patients. However in individual patients even in terminal renal failure a sustained regulatory feedback mechanism between serumerythropoietin concentration and hematocrit, probably working at lower hematocrit level, could be demonstrated.