Monoclonal antibodies: pharmacokinetics as a basis for new dosage regimens?

Complete monoclonal IgG antibodies which are in use in clinical practice share some pharmacological properties resulting in high concentrations in plasma. This fact is reflected in their low volumes of distribution, which can also be correlated with a high molecular weight and water solubility. This feature allows a novel approach to be applied to the dosing schedule for this group of drugs with fixed doses being used instead of the initially developed weight- or body surface-adjusted dosing schedules. In addition, the development of a new formulation containing hyaluronidase allows a subcutaneous route of administration to be used, because hyaluronidase creates a space in the subcutaneous tissue that helps antibody absorption. This method requires higher doses, but has allowed testing the feasibility of administering a fixed dose, with no individual dose adjustments based on weight or body surface. Moreover, loading doses are not needed, because the first dose results, within 3 weeks, in minimum concentrations that are higher than effective concentrations.

Antifungal prophylaxis with anidulafungin to minimize drug interactions with an antiepileptic treatment in a hematopoietic stem cell transplant recipient.

WHAT IS KNOWN AND OBJECTIVE: Invasive fungal infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). This provides a clear rationale for antifungal prophylaxis in this population. A concern is the potential for drug interactions, given that most of antifungals are metabolized through the P450 cytochrome system. CASE SUMMARY: We present a case of a 33-year-old woman, with a past history of high-risk epilepsy, who underwent allogeneic HSCT for a myelodysplastic syndrome. Anidulafungin was successfully used as antifungal prophylaxis to minimize drug interactions with her antiepileptic treatment. WHAT IS NEW AND CONCLUSION: This is the first reported case of antifungal prophylaxis with this echinocandin in HSCT. Anidulafungin may be an option in transplant recipients with multiple risk factors for drug interactions.

Daptomycin is safe and effective for the treatment of gram-positive cocci infections in solid organ transplantation.

INTRODUCTION: Infections caused by resistant gram-positive cocci (GPC), especially to glycopeptides, are difficult to treat in solid organ transplant (SOT) recipients as a result of lower effectiveness and high rates of renal impairment. The aim of this study was to evaluate the use of daptomycin in this population. METHODS: Over a 2-year period (March 2008-2010) in 9 Spanish centers, we enrolled all consecutive recipients who received daptomycin to treat GPC infection. The study included 43 patients, mainly liver and kidney transplant recipients. RESULTS: The most frequent infections were catheter-related bacteremia caused by coagulase-negative staphylococci (23.2%), skin infection caused by Staphylococcus aureus (11.5%), and intra-abdominal abscess caused by Enterococcus faecium (20.9%). The daily daptomycin dose was 6 mg/kg in 32 patients (74.4%). On day 7 of daptomycin treatment, median estimated area under the curve was 1251 µg/mL/h. At the end of follow-up, analytical parameters were similar to the values at the start of therapy. No changes were observed in tacrolimus levels. No patient required discontinuation of daptomycin because of adverse effects. Clinical success at treatment completion was achieved in 37 (86%) patients. Three patients died while on treatment with daptomycin. CONCLUSION: In summary, daptomycin was a safe and useful treatment for GPC infection in SOT recipients.

Economic impact of managing invasive mold disease with isavuconazole compared with liposomal amphotericin B followed by posaconazole in Spain.

BACKGROUND: Invasive fungal infections (IFI) are associated with significant morbidity and mortality. The objective of this work was to compare the costs per adult patient, associated with intravenous isavuconazole (ISAV) followed by oral ISAV versus the regimen of liposomal amphotericin B followed by posaconazole (L-AMB→POSA) in the treatment of IFI. The comparison was conducted from the perspective of the Spanish National Health System (SNS). METHODS: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration, hospitalization, laboratory tests and adverse events costs were evaluated from SNS perspective. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: Total costs per-patient were €24,715.54 with ISAV versus €29,753.53 with L-AMB→POSA, resulting in cost-savings per patient treated with ISAV of €5,037.99 (-16.9%). Treatment costs of IFI remained lower for ISAV than for L-AMB→POSA across all sensitivity analyses (-7,968.89€ to -326.59€), being treatment duration the most influential parameter. CONCLUSION: According to the present model, the treatment of IFIs with ISAV would generate savings for the SNS compared to L-AMB→POSA. These savings are attributed to the shorter duration of IV treatment, reduced use of healthcare resources and lower costs associated with managing adverse effects when ISAV was employed.

Recommendations on the use of azole antifungals in hematology-oncology patients.

The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

Interactions listed in the Paxlovid fact sheet, classified according to risks, pharmacological groups, and consequences.

Paxlovid (nirmatrelvir plus ritonavir) is a new oral antiviral therapeutic for the treatment and post-exposure prophylaxis of COVID-19. Nirmatrelvir is an inhibitor of SARS-CoV-2 main protease, while ritonavir is used as a CYP3A inhibitor in low doses to slow the metabolism of nirmatrelvir, thus enhancing their therapeutic effect. The isoenzyme CYP3A4 is responsible for at least part of the oxidative metabolism of approximately 60% of available medications and ritonavir is therefore a significant source of drug interactions. We describe here the drugs that are contraindicated or should be used with or without precautions when Paxlovid (nirmaltrevir plus ritonavir) should be administered according to each fact sheet in force at the Spanish Agency for Medicines and Health Products.

Recommendations for antibiotic selection for severe nosocomial infections.

Severe infection and its evolution to sepsis are becoming more prevalent every day and are among the leading causes of critical illness and mortality. Proper management is crucial to improve prognosis. This document addresses three essential points that have a significant impact on this objective: a) early recognition of patients with sepsis criteria, b) identification of those patients who suffer from an infection and have a high risk of progressing to sepsis, and c) adequate selection and optimization of the initial antimicrobial treatment.

[Recommendations of antifungal treatment in patients with low grade immunosuppression]. / Recomendaciones de tratamiento antifúngico en pacientes con bajo grado de inmunodepresión.

Because of the relevance that the systemic mycoses has acquired in non-highly immunocompromised patients, the treatment difficulties they have due to the increase of the non-albicans Candida species and the need to have a better and more rational use of the new antifungal agents (voriconazole, posaconazole, caspofungin, anidulafungin and micafungin), an experts' panel on infectious diseases in representation of the Spanish Society of Chemotherapy, Spanish Society of Internal Medicine, and Spanish Society of Pneumology and Thoracic Surgery has met in order to make a few recommendations based on the scientific evidence in an effort to improve their efficiency.

Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy.

Pseudomonas aeruginosa is characterized by a notable intrinsic resistance to antibiotics, mainly mediated by the expression of inducible chromosomic ß-lactamases and the production of constitutive or inducible efflux pumps. Apart from this intrinsic resistance, P. aeruginosa possess an extraordinary ability to develop resistance to nearly all available antimicrobials through selection of mutations. The progressive increase in resistance rates in P. aeruginosa has led to the emergence of strains which, based on their degree of resistance to common antibiotics, have been defined as multidrug resistant, extended-resistant and panresistant strains. These strains are increasingly disseminated worldwide, progressively complicating the treatment of P. aeruginosa infections. In this scenario, the objective of the present guidelines was to review and update published evidence for the treatment of patients with acute, invasive and severe infections caused by P. aeruginosa. To this end, mechanisms of intrinsic resistance, factors favoring development of resistance during antibiotic exposure, prevalence of resistance in Spain, classical and recently appeared new antibiotics active against P. aeruginosa, pharmacodynamic principles predicting efficacy, clinical experience with monotherapy and combination therapy, and principles for antibiotic treatment were reviewed to elaborate recommendations by the panel of experts for empirical and directed treatment of P. aeruginosa invasive infections.

Pharmacokinetic/pharmacodynamic serum and urine profile of cefditoren following single-dose and multiple twice- and thrice-daily regimens in healthy volunteers: a phase I study.

The objectives of this randomized, double-blind study were to evaluate the pharmacokinetics, and the pharmacodynamic and gastrointestinal (GI) tolerance of cefditoren pivoxil in healthy adult male volunteers when it is administered three times a day. Twenty healthy volunteers were included in the study. On day 1, 10 subjects received a 200-mg single dose of cefditoren pivoxil and 10 received a 400-mg dose. After a washout period of 8 days, eight subjects received cefditoren pivoxil 400 mg b.i.d., eight received 400 mg t.i.d., and four received placebo for 10 days. Medication was taken 30 min after meals. Blood and urine collections were carried out on days 1, 9, 14 and 19. Volunteers were asked about any GI change, especially about bowel habits, nausea, vomiting and abdominal pain. The maximum cefditoren concentration (C(max)) had a mean value of 3.77+/-0.66 mg/l, and was reached between 1.5 and 3 h in the thrice-daily administration. In the twice-daily regimen, the C(max) was 3.27+/-0.64 mg/l. The mean time above breakpoint minumum inhibitory concentration (MIC), calculated with data from each pharmacokinetic profile, was always above 40%, in both the twice- and thrice-daily regimens. The half-life of cefditoren was 1.19+/-0.2 h and 1.36+/-0.2 h in the twice-daily and thrice-daily regimens, respectively. The C(max) of cefditoren in urine was reached between 2 and 4 h postadministration, with a mean value of 154.53 mg/l in the twice-daily regimen, and 186.59 mg/l in the thrice-daily administration. There were no differences between the groups in the incidence of GI adverse events. The present data show that the administration of cefditoren pivoxil 400 mg t.i.d. is possible because it is well tolerated, and it increases the probability of success when the MIC of the causative bacteria is close to the susceptibility breakpoint. The high concentrations of active drug in the urine enable cefditoren to be considered as a useful candidate for the treatment of uncomplicated urinary tract infections (UTIs).

[The most common infections in the transplanted patient]. / Infecciones más comunes en el paciente trasplantado.

Organ transplantation has become one of the most important areas of medical research and, at present, is still the only therapeutical tool for several diseases. However, there are a number of factors related to transplantation, like immunosuppression and prolonged neutropenia that affect the incidence of infection. These infections are somehow peculiar to transplant recipients. In fact, there are infectious diseases that only occur in immunodepression situations and, moreover, clinical expression of these infectious diseases can be quite different from that in immunocompetent patients. Besides these aspects, some infections, due to the high prevalence described, must be considered for prevention strategies because they continue to be a principal cause of morbidity and mortality, either due to direct effects or to their implication in the pathogenesis of rejection. These strategies commence before transplantation by active immunization through vaccine administration to the patient and to people in the milieu and continue after transplantation with prophylaxis or pre-emptive therapy. The importance of infectious diseases in the evolution and prognosis of transplant recipients gives a special meaning to the understanding of associated infections, their clinical expression and ways of prevention and treatment.

A multicenter double-blind study comparing lovastatin and gemfibrozil in the treatment of primary hypercholesterolemia.

The efficacy and tolerability of lovastatin and gemfibrozil were compared in a randomized double-blind 12-week study including 182 patients with primary hypercholesterolemia, from 7 hospitals in Spain. Inclusion criteria were total-cholesterol of at least 250 mg/dl and triglycerides less than 350 mg/dl. Patients were stratified in two groups: group 1, cholesterol less than 300 mg/dl, and group II, cholesterol equal to or more than 300 mg/dl. Patients were randomized to gemfibrozil (600 mg b.i.d.) or lovastatin (20 mg q.p.m., group I and 40 mg q.p.m., group II). If after 6 weeks of treatment cholesterol remained above 200 mg/dl, lovastatin does were doubled. In group I, lovastatin decreased cholesterol by 20%, LDL-C by 28%, and triglycerides by 17%, and increased HDL-C by 8%. In group II the results were: -26%, -33%, -19% and +6% respectively. The corresponding results with gemfibrozil were: -8%, -9%, -28% and +14% (group I); and -13%, -14%, -33% and +9% (group II). In both groups, lovastatin was more effective in reducing cholesterol and LDL-C (P less than 0.001) and gemfibrozil in reducing triglycerides (P less than 0.05 group I and P less than 0.01 group II). Both drugs were well tolerated. Thus, lovastatin and gemfibrozil are effective lipid-lowering agents; lovastatin has more pronounced effects in patients with hypercholesterolemia.

Relationship between pharmacokinetics and pharmacodynamics of beta-lactams and outcome.

The in-vitro susceptibility of an organism and the pharmacokinetics of an antimicrobial agent are two basic factors on which the choice of standardised treatment regimens is based. However, the inter-individual variability of these factors, which modifies the exposure of bacteria to an antibiotic in terms of time and quantity, is not usually taken into account. In 87 patients treated with beta-lactams (ceftriaxone, cefepime or piperacillin), the probability of failure was greater when the infectious process was located in tissues with barriers to the distribution of beta-lactams. Mean MICs of piperacillin and cefepime, but not ceftriaxone, were below the breakpoints in cases of both recovery and failure, but organisms isolated from patients with a poor outcome had higher MICs. Therefore, the use of breakpoints to determine the susceptibility of microorganisms was not satisfactory in predicting the outcome for a large number of patients. If MICs are determined and plasma concentrations are monitored, dosages can be adjusted according to these parameters, thereby allowing antibiotic treatment to be individualised.

Cimetidine does not alter sparfloxacin pharmacokinetics.

The interaction between cimetidine and sparfloxacin was studied in 10 healthy volunteers who received a single oral dose of 400 mg sparfloxacin on the third day of an 8 day cimetidine (400 mg t.i.d.) or placebo randomly assigned treatment. No statistically significant differences were observed in the pharmacokinetic parameters (Cmax-AUC-T1/2-urinary excretion and metabolic ratio) of sparfloxacin following the 2 treatment. Cimetidine does not affect absorption, metabolism or urinary excretion of sparfloxacin; consequently, patients exposed to this drug combination are not at risk.

Clinical relevance of sirolimus drug interactions in transplant patients.

Sirolimus, a new immunosuppressant drug; is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of the P-glycoprotein drug efflux pump. The CYP3A4/P-glycoprotein system is mainly localized in the liver and intestine. It is responsible for the severe first pass metabolism of sirolimus with a low bioavailability. Drugs like voriconazole, itraconazole, fluconazole, and erytrhomycin may decrease the metabolic activity of this enzymatic system. This report documents in five patients that coadministration of these antimicrobials with sirolimus increases the blood concentrations of the immunosuppressant. The dose-normalized trough blood concentration showed a mean increase of sevenfold with the coadministration of these drugs. It is essential to monitor the blood sirolimus concentrations and to adjust the sirolimus doses before and after coadministration of these drugs.

Open cross-over comparison of tulobuterol and fenoterol in asthmatic adult patients.

The objective of this open randomized cross-over study was to compare the clinical efficacy and safety of a recently introduced beta-2 mimetic, tulobuterol, with fenoterol in asthma patients. The study length was four weeks with each drug, with a seven-day washout period between treatment courses. Spirometric tests were carried out every 14 days; laboratory tests and an electrocardiograph were performed at the beginning and end of each treatment course, and a daily diary of salbutamol aerosol use and adverse reactions was kept. Pulmonary function tests and registration of pulse rate and arterial pressure were performed on days 1, 14 and 28 of both treatment courses, before the morning dose and 3 h after administration of the drug. No statistically significant changes were detected in laboratory tests, pulse rate or arterial pressure. The only adverse reaction noted was transient tremor which appeared in three cases with tulobuterol and in two cases with fenoterol. Spirometric tests revealed increases in all parameters with both drugs, although in the comparison between groups no overall statistically significant differences were found. All patients required inhaled salbutamol with both of the drug treatments, and there was a significant increase (p less than 0.05) in its use during the fenoterol treatment course. With both tulobuterol and fenoterol, inhaled salbutamol was mainly used within 2 h before and 1 h after each dose. It is concluded that tulobuterrol (2 mg, twice daily) was at least as effective as fenoterol (2.5 mg, thrice daily), while its clinical effect was longer-lasting. It is doubtful, however, that it provides coverage for 12 h in the type of patients selected.

[Double-blind parallel clinical trial with tenoxicam in comparison with indomethacin in the treatment of rheumatoid arthritis]. / Ensayo clínico, paralelo, doble ciego con el tenoxicam frente a indometacina en el tratamiento de artritis reumatoide.

The comparative effects of tenoxicam and indomethacin are studied in 20 patients with rheumatoid arthritis. Ten evolutive parameters were studied after six weeks of treatment. Both drugs showed similar tolerance and efficacy on the evolution of the disease.

[Treatment with tacrolimus in autoimmune diseases]. / Posibles indicaciones del tratamiento de las enfermedades autoinmunes con tacrolimus.

Tacrolimus is an immunosuppressive drug used most successfully as a primary drug to suppress the rejection of transplants. Tacrolimus may also be useful as a novel therapy for autoimmune disease. There are various reports in the bibliography about the use of tacrolimus in the treatment of some autoimmune diseases: inflammatory bowel disease, autoimmune hepatitis, cutaneous, neurologic, renal, endocrine or eye disease. In this review of more than 130 papers, we discuss the rationale for the use of tacrolimus in autoimmune disease and report the clinical experience with the drug in the management of a variety of autoimmune diseases. But, although there are a lot questions that require future research (dose, duration of treatment, when to begin tacrolimus treatment, how to monitor it, etc.), there is also wide experience with tacrolimus in the treatment of this type of disease.

[Phase I study of a tolmetin-paracetamol (AU-8001) ester]. / Estudio en fase I de un éster de tolmetín y paracetamol (AU-8001).

A cross-over study of a tolmetin-paracetamol ester was performed on 6 healthy females. The low biodisponibility obtained might preclude its therapeutic use.

[The antihypertensive efficacy and tolerance of bopindolol (LT 31-200) in hypertensive patients]. / Estudio de la eficacia antihipertensiva y tolerancia del bopindolol (LT 31-200) en pacientes hipertensos.

A open study with increasing doses of bopindolol, a nonselective beta-blocker of long half-life has been carried out in patients with mild and moderate hypertension in order to assess the efficacy and security of the treatment in short and long term. Twenty patients (22 women and 8 men) were included with the ranging ages from 36 to 62 years old (x +/- SD 51.6 +/- 7.6) whose blood pressures were higher than 160 mm Hg for the systolic value and between 90 and 125 mm Hg for the diastolic (x +/- SD 165 +/- 7.2 and 102.6 +/- 6.7 respectively). Nineteen from the twenty patients (95%) responded satisfactorily after 20 weeks of oral bopindolol treatment once a day showing significative statistical differences on forth week of the treatment versus blood pressure rates of placebo's period. Similar results were obtained with regard to the cardiac frequency. HDL cholesterol rates increased significantly as well as the ratio HDL cholesterol/total cholesterol.