Oral Tolerability Research Articles

Impact of a program to promote sequential therapy with paracetamol and omeprazole

BackgroundOral route is safer and less costly than intravenous route; however, sometimes intravenous therapy is used longer than necessary. Paracetamol and omeprazole are two widely used drugs in hospitalised patients...

The Pharmacokinetics, Pharmacodynamics, and Safety of Orally Dosed INCB018424 Phosphate in Healthy Volunteers

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 C(max) by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.

The Relationship Between Patient-Reported Tolerability Issues With Oral Antidiabetic Agents and Work Productivity Among Patients Having Type 2 Diabetes

To investigate the association between reported oral antidiabetic tolerability issues and work productivity, activity impairment, and indirect costs. Data were collected from the 2006 to 2008 US National Health and Wellness Survey and the Lightspeed Research, using an Internet-based questionnaire (N = 2074). Absenteeism, presenteeism, overall work impairment, and activity impairment increased as the number of tolerability issues increased. Similar results were observed using a diabetes-specific productively measure. Total annual adjusted indirect costs (absenteeism and presenteeism costs summed) were $2759, $5533, $7537, and $8405 for patients with 1, 2, 3, and 4 or more tolerability issues, respectively. The consideration of tolerability profiles of oral antidiabetic agents may lead to improved productivity among treated patients. Furthermore, targeted educational programs regarding risks and management of these issues to employees with type 2 diabetes mellitus may benefit both employers and patients.

Eficácia, tolerabilidade e segurança do uso do sirolimo após o transplante renal

INTRODUCAO: Sirolimo (SRL) e um imunossupressor com conhecida eficacia e perfil de seguranca na profilaxia da rejeicao aguda apos o transplante renal. OBJETIVOS: Avaliar eficacia, tolerabilidade e seguranca do uso do SRL e de prednisona em associacao a ciclosporina (CSA) ou tacrolimo (TAC) apos o transplante renal. METODOLOGIA: Estudo retrospectivo de 332 receptores de transplantes renais realizados entre 1999 e 2006. O desfecho primario foi a falha de tratamento, definida como a incidencia cumulativa de rejeicao aguda confirmada por biopsia (RACB), perda do enxerto, obito ou descontinuacao do SRL. RESULTADOS: Dos 332 transplantes, 92% foram com doador vivo. A media de idade dos receptores foi de 37 anos, sendo 65% homens, 46% brancos e 6% diabeticos. SRL foi associado a CSA ou TAC em 70,8% e 29,2% dos pacientes. A incidencia de falha de tratamento foi de 22,2% e de 47,8% no final do primeiro e do quinto ano de transplante, sem diferenca entre pacientes recebendo CSA ou TAC. Ao final do quinto ano, as sobrevidas do paciente, do enxerto, do enxerto censorando o obito e livre de RACB foram de 92,8%, 86,1%, 92,7% e 82,2%, respectivamente. O tratamento com SRL foi interrompido em 27,1% dos pacientes: 22,9% em razao de reacoes adversas e 3,3% devido a ineficacia. Os principais motivos de suspensao do SRL foram dislipidemia (6,0%), disfuncao do enxerto (5,2%), proteinuria (4,5%), infeccoes (1,5%), dificuldade de cicatrizacao (1,2%) e anemia (0,9%). CONCLUSAO: Na populacao estudada, a eficacia e a seguranca do SRL foram semelhantes quando combinado com CSA ou TAC. A tolerabilidade oral foi adequada considerando-se a relativa baixa taxa de interrupcao do uso de SRL.

Análogos de nucleósidos y nucleótidos en el tratamiento de la hepatitis crónica por el virus B

At least 4 nucleos(t)ide analogs have been approved for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, entecavir, and telbivudine. The introduction of these drugs has radically changed the treatment of this disease. The advantages of these drugs are their oral administration, excellent tolerability and efficacy in all types of chronic hepatitis B (compensated and decompensated disease). The limitations are the need for prolonged treatments, which hampers adherence and can cause selection of HBV strains resistant to distinct drugs. The resistance rate differs for each of the drugs. Nucleotide analogs such as adefovir and tenofovir are useful in patients resistant to nucleoside analogs such as lamivudine, entecavir and telbivudine and vice versa. In cases of resistance to one of these drugs, combined treatment is advised.

Cost-Effectiveness and Patient Tolerance of Low-Attenuation Oral Contrast Material: Milk Versus VoLumen

The purpose of our study was to prospectively compare the cost, effectiveness, and patient tolerance of milk and VoLumen, a 0.1% barium suspension, in patients undergoing abdominal and pelvic CT with oral and i.v. contrast media. Two hundred fifteen consecutive outpatients were randomly assigned to receive either whole milk (n = 115) or VoLumen (n = 100). Results were independently reviewed by two radiologists who were blinded to the oral contrast agent used. Degree of bowel distention was qualitatively scored on a 4-point scale, and bowel wall visibility was graded qualitatively on a yes-or-no basis. A questionnaire regarding oral contrast tolerability was provided to each patient. Cost comparison of the two agents was performed. No statistically significant differences were seen between whole milk and VoLumen with respect to degree of bowel distention and mural visualization for all segments of bowel studied (p > 0.05 for both reviewers). Significantly more patients ranked milk as pleasant in taste compared with VoLumen (p < 0.0001). More patients preferred milk compared with VoLumen (p < 0.0001). Milk was better tolerated than VoLumen, with fewer abdominal side effects, including abdominal discomfort (p = 0.019), cramping (p = 0.019), nausea (p = 0.016), and diarrhea (p = 0.0002). The cost per patient for VoLumen is $18 compared with $1.48 for milk. Whole milk is comparable to VoLumen with respect to bowel distention and bowel wall visualization and has a lower cost, better patient acceptance, and fewer adverse symptoms. Milk is a cost-effective alternative to VoLumen as a low-attenuation oral contrast agent.

(190) The safety of BEMA (BioErodible MucoAdhesive) fentanyl use for breakthrough pain (BTP) in cancer patients

The BEMA drug delivery system was designed to improve oral transmucosal dosing reliability, tolerability, and patient acceptance. The mucoadhesive polymers adhere and deliver fentanyl across the capillary rich mucosa. Two-hundred twenty (220) adult opioid-tolerant patients with chronic cancer pain who experienced one to four daily episodes of BTP while on stable opioid doses (i.e., a daily dose equal in analgesic activity to at least 60 mg of oral morphine) received BEMA fentanyl in an open-label, multicenter study.

Pharmacokinetics and Safety of Montelukast Oral Granules in Children 1 to 3 Months of Age With Bronchiolitis

The single-dose pharmacokinetics of montelukast 4-mg oral granules and tolerability of daily administration of 2 different doses of montelukast (4 mg and 8 mg given once daily for 7 days) versus placebo were evaluated in 12 infants 1 to 3 months of age with bronchiolitis or a history of bronchiolitis and asthma-like symptoms. The population area under the concentration-time curve estimate after a single 4-mg dose of montelukast was 13 195.7 +/- 2309.8 (standard error) ng.hr/mL, 3.6 times higher than historical values in infants 3 to 24 months of age. Six patients had 10 total clinical adverse experiences; none was considered serious or drug related. Three patients had transient drug-related increases in aspartate aminotransferase (montelukast 8 mg [n = 2]; placebo [n = 1]). Despite increased systemic exposure after administration of a single dose of montelukast 4-mg oral granules in infants 1 to 3 months of age compared with that in pediatric patients 3 to 24 months of age, administration of montelukast at 4 and 8 mg once daily for 7 days in 1- to 3-month-old infants was generally well tolerated.

(191) Dose linearity and absolute bioavailability of BEMA (BioErodible MucoAdhesive) fentanyl in healthy volunteers

Oral transmucosal delivery of fentanyl is a rapid and proven route of administration for the management of breakthrough pain in cancer patients.1,2 The BEMA drug delivery system was designed to improve oral transmucosal dosing reliability, tolerability and patient acceptance. This bilayer polymer delivery system can control the mucosal surface application area and time in contact with the mucosa, optimizing delivery and pharmacokinetics of buccally delivered fentanyl. The linearity of plasma fentanyl concentrations across a range of doses and the absolute bioavailability of fentanyl were explored in two Phase 1 pharmacokinetic studies.

(192) Lack of adverse events affecting the mouth in three clinical trials of BEMA (BioErodible MucoAdhesive) fentanyl

The BEMA drug delivery system was designed to improve oral transmucosal dosing reliability, tolerability, and patient acceptance. BEMA fentanyl is a bilayer polymer drug delivery system with a mucoadhesive layer that delivers fentanyl across the capillary rich buccal mucosa. The entire dosage form dissolves within 15-30 minutes of application. Safety data were combined from three BEMA fentanyl clinical trials (a trial in cancer patients with and without mucositis, a double-blind crossover study of efficacy in cancer patients with breakthrough pain, and a long-term safety study).

A Randomized, Placebo-controlled Study of Fentanyl Buccal Tablet for Breakthrough Pain in Opioid-treated Patients With Cancer

Cancer-related breakthrough pain (BTP) is typically managed with a short-acting oral opioid, taken as needed during a fixed-schedule opioid regimen. The conventional approach may not provide the onset of analgesia required for BTP for many patients, because the onset of analgesia with short-acting opioids lags behind the time course of the majority of episodes of BTP. The fentanyl buccal tablet (FBT) employs a novel delivery system that enhances the rate and extent of absorption of fentanyl through the buccal mucosa. This double-blind, randomized, placebo-controlled study evaluated the efficacy, safety, and tolerability of FBT in opioid-treated patients with cancer-related BTP. After an open-label titration (N=123) to identify an effective FBT dose to treat BTP episodes, 77 patients were randomly assigned to 1 of 18 prespecified dose sequences of 10 tablets (7 FBT and 3 placebo). Pain intensity, pain relief (PR), and global performance of the medication were recorded at regular time intervals between 15 and 60 minutes. Pain intensity differences (PID), the summed PID (SPID), and summed total PR were calculated. The SPID at 30 minutes (SPID30) was the primary efficacy variable. Adverse events were reported. Sixty-five percent (80/123) of patients were titrated to an effective dose. The mean (SE) SPID30 for FBT was 3.0+/-0.12 versus 1.8+/-0.18 for placebo (P<0.0001). Measures of PR, PID, SPID, summed total PR, and patient ratings of global performance of medication significantly favored FBT over placebo at all time points. Adverse events were typical of opioid drugs. Poor oral tolerability was noted in 2 patients. FBT is efficacious and safe in the treatment of cancer-related BTP.

TRIPSTAR: prioritizing oral triptan treatment attributes in migraine management.

Migraine can be associated with severe pain and is often very disabling. Optimal treatment should provide rapid and sustained, complete pain relief, be well tolerated and restore normal function. The seven commercially available triptans show differences in performance on individual treatment attributes. The TRIPSTAR multiattribute decision model compares the profiles of the oral triptans, using efficacy and tolerability data weighted for importance, to identify if measurable differences are clinically relevant. Application of the TRIPSTAR model was demonstrated at the Migraine Trust International Symposium 2002, where delegates collectively prioritized treatment attributes according to the needs of a specific patient case history. The TRIPSTAR model identified the preferred triptans for this patient. These three triptans, almotriptan 12.5 mg, eletriptan 80 mg and rizatriptan 10 mg, standout in a triptan meta-analysis, three TRIPSTAR surveys and in a demonstration of the TRIPSTAR model at a symposium in the USA. Taken together the findings suggest that some differences amongst triptans may be relevant in clinical practice.

Professional Vital Bleaching Using a Thin and Concentrated Peroxide Gel on Whitening Strips: An Integrated Clinical Summary

Rapid innovation in vital bleaching continues to expand the number of treatment options available to patients, particularly in the area of at-home whitening. The development of bleaching strips represented a new paradigm in the delivery of peroxide. The efficacy and safety of bleaching strip systems delivering up to 6.5% hydrogen peroxide has been established in numerous randomized clinical trials. In 2003, a novel bleaching strip with 14% hydrogen peroxide (Crest Whitestrips Supreme) was introduced. This advanced system carries a thinner but more concentrated gel on each strip, resulting in a relatively similar total amount of peroxide as compared to other strip systems. This 2-variable change, higher concentration gel with lowered gel volume translates to improved whitening without adversely affecting oral soft tissue tolerability and irritation. This paper provides an integrated review of 9 comparative clinical trials evaluating the whitening response (six trials) and safety (nine trials) of this novel vital bleaching system. Efficacy results for the 14% hydrogen peroxide strips were significantly (p<0.05) better than the placebo or pooled positive controls evaluated in the clinical trials assessing tooth color or shade. Adverse events were similar in type to the other vital bleaching systems. Overall, the research of 408 patients showed generally better efficacy and similar to or better tolerability for the 14% hydrogen peroxide strips compared to a selected group of marketed positive bleaching controls.

Development of Tridentate Iron Chelators: From Desferrithiocin to ICL670

Successful treatment of beta-thalassemia requires two key elements: blood transfusion and iron chelation. Regular blood transfusions considerably expand the lifespan of patients, however, without the removal of the consequential accumulation of body iron, few patients live beyond their second decade. In 1963, the introduction of desferrioxamine (DFO), a hexadentate chelator, marked a breakthrough in the treatment of beta-thalassemia. DFO significantly reduces body iron burden and iron-related morbidity and mortality. DFO is still the only drug for general use in the treatment of transfusion dependent iron overload. However, its very short plasma half-life and poor oral activity necessitate special modes of application (subcutaneous or intravenous infusion) which are inconvenient, can cause local reactions and are difficult to be accepted by many patients. Over the past four decades, many different laboratories have invested major efforts in the identification of orally active iron chelators from several hundreds of molecules of synthetic, microbial or plant origin. The discovery of ferrithiocin in 1980, followed by the synthesis of the tridentate chelator desferrithiocin and proof of its oral activity raised a lot of hope. However, the compound proved to be toxic in animals. Over a period of about fifteen years many desferrithiocin derivatives and molecules with broader alterations led to the discovery of numerous new compounds some of which were much better tolerated and were more efficacious than desferrithiocin in animals, however, none was safe enough to proceed to the clinical use. The discovery of a new chemical class of iron chelators: The bis-hydroxyphenyltriazoles re-energized the search for a safe tridentate chelator. The basic structure of this completely new chemical class of iron chelators was discovered by a combination of rational design, intuition and experience. More than forty derivatives of the triazole series were synthesized at Novartis. These compounds were evaluated, together with more than 700 chelators from various chemical classes. Using vigorous selection criteria with a focus on tolerability, the tridentate chelator 4-[(3,5-Bis-(2-hydroxyphenyl)-1,2,4)triazol-1-yl]-benzoic acid (ICL670) emerged as an entity which best combined high oral potency and tolerability in animals. ICL670 is presently being evaluated in the clinic.

Phase I studies of ZD1839 in patients with common solid tumors

Clinical development of ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) was initiated based on strong preclinical studies that showed antitumor responses in a variety of solid tumor types and established its oral bioavailability and tolerability. In phase I trials, ZD1839 was investigated in patients with a wide variety of solid tumors that commonly express epidermal growth factor receptor–tyrosine kinase. More than 250 patients with advanced refractory disease were enrolled in phase I studies; of these, 100 had non–small cell lung cancer (NSCLC). All patients had been recipients of substantial prior therapy. Intermittent and continuous dosing schedules with ZD1839 were well tolerated by these patients for up to 6 months or more. The most frequently reported adverse events were grade 1 or 2 diarrhea and grade 1 or 2 acneiform rash; these effects were reversible on discontinuation of therapy and either required no management or were easily managed. Grade 3 or 4 adverse events were rare and most were attributed to disease progression rather than being drug related. In phase I trials, the maximum tolerated dose of ZD1839 was determined to be 700 to 1000 mg/day; diarrhea was found to be the dose-limiting toxicity. Pharmacokinetic profiles supported once-daily oral dosing and indicated that biologically active plasma concentrations were achieved at the doses studied. Pharmacodynamic results in skin biopsies showed that ZD1839 produced inhibition of epidermal growth factor receptor–tyrosine kinase in these patients. Durable tumor responses and stable disease were observed with ZD1839 treatment in patients with advanced NSCLC. Symptoms related to NSCLC also appeared to improve rapidly in some patients. Prolonged time on therapy was observed for other tumor types in addition to NSCLC, including hormone-refractory prostate, colorectal, head and neck, breast, ovarian, and renal cancers. The promising phase I results observed in heavily pretreated patients with advanced NSCLC and other solid tumors have warranted investigation in phase II/III clinical trials in these populations. Phase II/III trials are being conducted in patients with advanced NSCLC. Phase II trials of ZD1839 are also being conducted in patients who have hormone-refractory prostate, breast, or colorectal cancer, as well as other solid tumors. Based on the phase I study results, once-daily oral doses of 250 mg and 500 mg, which are well below the maximum tolerated dose, were selected for further clinical investigation of ZD1839. Semin Oncol 30 (suppl 1):21:29. Copyright 2003, Elsevier Science (USA). All rights reserved.

Bone disease in myeloma.

The major clinical manifestation of multiple myeloma results from osteolytic bone destruction. The only currently Food and Drug Administration-approved drug for the treatment of the bony complications of multiple myeloma is monthly intravenous pamidronate at a dose of 90 mg infused over 4 hours. Recent studies have shown the safety of 2-hour infusions. A randomized trial comparing pamidronate to placebo continued to show benefits throughout the 21-month trial. Although the duration of therapy has not been firmly determined, it is likely that discontinuation of this drug will be met by enhanced bone loss and an increased risk of bony complications for these patients. Thus, it is recommended that the drug be continued indefinitely. Support for this recommendation also comes from the reduced bone density observed in women with postmenopausal osteoporosis following the withdrawal of bisphosphonate treatment. Recent attempts to give higher doses, more frequent infusions (every 2 weeks or less), or more rapid infusions (1 hour or less) of pamidronate have occasionally been associated with albuminuria and azotemia. These modifications should therefore be avoided. Importantly, the drug can be safely administered at 90 mg monthly to patients with poor renal function. The use of pamidronate for myeloma patients without lytic bone involvement or with Durie-Salmon stages I or II disease has not been evaluated. However, it is recognized that most patients with earlier stages of disease or without lytic bone involvement also develop bony complications. There is no reason to believe that these patients would not benefit from monthly intravenous infusions of pamidronate. The potential antimyeloma effect of this agent is another reason to administer this drug in these types of patients. Thus, it is our practice to administer monthly pamidronate to myeloma patients regardless of stage or bone involvement. However, trials evaluating oral bisphosphonates have produced inconsistent clinical results, probably as a result of the erratic and scanty poor absorption as well as poor oral tolerability of these drugs. Although these oral agents may be useful in some patients, it is impossible to identify which myeloma patients will benefit from orally administered bisphosphonates. The more potent nitrogen-containing bisphosphonate zoledronic acid more effectively reverses hypercalcemia of malignancy than pamidronate, and it appears promising in reducing bone loss in cancer patients. However, its efficacy in preventing skeletal complications is still being evaluated. Many other types of new agents are in early clinical trials, but their efficacy remains unproven at the present time.

Observations on oral Sultamicillin/Unasyn CP-45 899 therapy of neonatal infections

The use of an effective antimicrobial remains a problem in the neonate, thereby necessitating empiric combinations of parenteral agents. We therefore studied oral Sultamicillin's (Unasyn CP-45 899) efficacy and tolerability (dose = 50 mg/kg per day) in the treatment of serious infections in 27 neonates over an 18 month period. The study cohort comprised newborns with suspected or confirmed infections in the Special Care Baby Unit of a referral hospital. The infants with overwhelming/severe infections or proven/suspected renal, hepatic or hematologic disease; or known hypersensitivity to penicillins or any β-lactams were excluded. There were 12 babies with skin and soft-tissue infections, although pneumonia [11] was most predominant in our series. Bacterial isolates were mainly Staphylococcus aureus, Escherichia Coli and Klebsiella pneumoniae with a β-lactamase production rate of 88%. The clinical cure and improvement rates were 96.3 and 100%, respectively and the evaluable bacteriologic cure-rate was 93.8%. The mean (S.D.) duration of therapy was 7.4 (2.6) days (range, 4–14) with significant resolution of features occurring within a 48 h period ( 24 27 , P < 0.01). No serious adverse/side effects were seen as only one (3.7%) experienced mild loose stools. We show with these prospective observations (our cohort albeit small) that sultamicillin orally is efficacious, tolerable and safe for treating of mild to moderate infections in the newborn caused by both gram-positive and gram-negative pathogens.