Pharmacokinetic and Pharmacodynamic Considerations of Antibiotic Use in Neonates.

The selection of an appropriate dose of a given antibiotic for a neonate not only requires knowledge of the drug's basic pharmacokinetic (PK) and pharmacodynamic (PD) properties but also the profound effects that organ development might have on the volume of distribution and clearance, both of which may affect the PK/PD of a drug. Interest has grown in alternative antibiotic dosing strategies that are better aligned with the antibiotic's PK and PD properties. These strategies should be used in conjunction with minimum inhibitory concentration measurements and therapeutic drug monitoring to measure their potential success.

Pharmacokinetic study of two different rifabutin doses co-administered with lopinavir/ritonavir in African HIV and tuberculosis co-infected adult patients.

Background: This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection.

Pharmacokinetics of plasma lopinavir and ritonavir in tuberculosis-HIV co-infected African adult patients also receiving rifabutin 150 or 300 mg three times per week.

Background: To evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and HIV co-infected adult patients.

Methods: This is a pharmacokinetic study conducted in Ouagadougou among patients treated with a standard dosage of LPV/RTV 400/100 mg twice daily and RBT 150 mg TPW (arm A = 9 patients) or rifabutin 300 mg TPW (arm B = 7 patients) based regimens. Patients were recruited from the Bogodogo and Kossodo district hospitals in Ouagadougou from May 2013 to December 2015.

Monoclonal Antibody Monitoring: Clinically Relevant Aspects, A Systematic Critical Review.

Monoclonal antibody (mAb) therapy does not usually lead to a clinical response in all patients and resistance may increase over time after repeated mAb administration. This lack or loss of response to the treatment may originate from different and little-known epigenetic, biomolecular, or pathophysiological mechanisms, although an inadequate serum concentration is perhaps the most likely cause, even if not widely recognized and investigated yet. Patient factors that influence the pharmacokinetics (PK) of a mAb should be taken into account.

Key Features Defining the Disposition of Bispecific Antibodies and Their Efficacy In Vivo.

Bispecific antibodies (BsAbs) are novel drugs, with only a few approved for clinical use. BsAbs are versatile molecules that come in many different forms and are designed and produced via genetic engineering. Although BsAbs share several pharmacokinetic (PK) and pharmacodynamic (PD) properties with monoclonal antibodies, they have their own unique characteristics based on their overall structure and specificities.

A New Enzyme-Linked Immunosorbent Assay for a Total Anti-T Lymphocyte Globulin Determination: Development, Analytical Validation, and Clinical Applications.

Background: Anti-T lymphocyte globulin (ATLG) modulates the alloreactivity of T lymphocytes, reducing the risk of immunological posttransplant complications, in particular rejection and graft-versus-host disease, after allogeneic hematopoietic stem cell transplantation (HSCT). We developed and validated a new enzyme-linked immunosorbent assay (ELISA) method to measure serum levels of total ATLG and evaluate the pharmacokinetics (PK) of the drug in children with β-Thalassemia, receiving allogeneic HSCT.

Methods: Diluted serum samples were incubated with Goat-anti-Rabbit IgG antibody coated on a microtiter plate and then, with Goat-anti-Human IgG labeled with horseradish peroxidase.

Bioequivalence of a New Oral Levosulpiride Formulation Compared With a Standard One in Healthy Volunteers.

Background: A monocentric, single-dose, open-label, 2-way, crossover randomized study was conducted by the San Matteo Phase I Clinical Trial Unit and Experimental Therapy (Pavia, Italy) to assess the bioequivalence and the systemic tolerability of a new oral formulation of levosulpiride (tablet 25 mg: test) versus a commercially available formulation on the Italian market (tablet 25 mg: reference).

Methods: Thirty-five healthy adult volunteers, men (n = 19) and women (n = 16), aged between 18 and 55 years were screened and 32 of them were enrolled in the study. After having signed the written informed consent, each subject received a single oral dose of Test or Reference product with 250 mL of natural mineral water, in fasting conditions, interspersed with a 6-day washout period Blood samples were collected up to 36 hours after drug administration: the drug plasma levels were determined by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

Pharmacokinetics of Colistin Following a Single Dose of Intravenous Colistimethate Sodium in Critically Ill Neonates.

In this study, we sought to evaluate the pharmacokinetics of colistin after intravenous administration of colistimethate sodium (CMS) in the critically ill neonates with Gram-negative bacterial infections. A single intravenous dose of CMS [approximately 150,000 IU/kg, equivalent to 5 mg/kg colistin base activity (CBA)] was administered to 7 critically ill neonates. Mean (±SD) maximum plasma colistin concentration and area under the time-concentration curve from 0 to infinity were 3.

Pulmonary and Systemic Pharmacokinetics of Colistin Following a Single Dose of Nebulized Colistimethate in Mechanically Ventilated Neonates.

The purpose of this study was to evaluate the pulmonary and systemic pharmacokinetics of colistin following a single dose of nebulized colistimethate sodium (CMS) in mechanically ventilated neonates. We administered a single dose of nebulized CMS (approximately 120,000 IU/kg of CMS, equivalent to 4 mg/kg colistin base activity) to 6 ventilated neonates with ventilator-associated pneumonia. The median gestational age was 39 weeks (range, 32-39 weeks).

A Comparison of Differences Between the Systemic Pharmacokinetics of Levobupivacaine and Ropivacaine During Continuous Epidural Infusion: A Prospective, Randomized, Multicenter, Double-Blind Controlled Trial.

Background: Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion.

Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease.

Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen.

Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins.

Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients.

Intraventricular or intrathecal colistin for the treatment of central nervous system infections caused by multidrug-resistant Gram-negative bacteria.

Central nervous system infections caused by Gram-negative bacteria susceptible only to colistin are rare but life-threatening and increasing in prevalence. Given the current antibiotic development pipeline it is likely that the paucity of therapeutic options will continue for the next years. Colistin is an amphipathic bactericidal antibiotic which is administered systemically as colistin methanesulfonate (also known as colistimethate sodium).

Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain.

Background: Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration.

Interindividual and intra-individual variabilities of darunavir and ritonavir plasma trough concentrations in multidrug experienced HIV patients receiving salvage regimens.

Background: There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited.

Aim: : To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response.

Methods: Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen.

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics.

The anti-CD20 antibody rituximab (RTX; Rituxan®, MabThera®) was the first anti-cancer antibody approved by the US Food and Drug Administration in 1997 and it is now the most-studied unconjugated therapeutic antibody. The knowledge gained over the past 15 y on the pharmacodynamics (PD) of this antibody has led to the development of a new generation of anti-CD20 antibodies with enhanced efficacy in vitro. Studies on the pharmacokinetics (PK) properties and the effect of factors such as tumor load and localization, antibody concentration in the circulation and gender on both PK and clinical response has allowed the design of optimized schedules and novel routes of RTX administration.

Genetic variability at COMT but not at OPRM1 and UGT2B7 loci modulates morphine analgesic response in acute postoperative pain.

Purpose: To investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms.

Methods: A total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry.

Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment: a hypothesis.

In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in more opportunistic infections. In a subgroup analysis of alemtuzumab trough levels during treatment by a sensitive enzyme-linked immunosorbent assay (ELISA) method, detectable levels were found in 4/6 complete and 0/3 partial responders. A relationship between alemtuzumab plasma levels, response and duration of lymphocytopenia was evident.

Pharmacokinetics, pharmacodynamics and clinical use of valganciclovir in newborns with symptomatic congenital cytomegalovirus infection.

Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v.

Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients.

Measurement of inosine-monophosphate dehydrogenase (IMPDH) activity or gene expression was used as a further approach in pharmacokinetics (PK)/pharmacodynamic (PD)-guided mycophenolate mofetil (MMF) therapy. Forty-four de novo kidney transplant patients were enrolled; 35 of these completed the study, and were followed for 24 weeks for clinical status, PK parameters, IMPDH activity and IMPDH1/2 gene expression. IMPDH activity and expression were measured in peripheral blood mononuclear cells before transplant and at week 2,4,12 and 24, drawn before (t0) and 2 h (t2 h) after MMF administration.

Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate.

Intraventricular colistin, administered as colistin methanesulfonate (CMS), is the last resource for the treatment of central nervous system infections caused by panresistant Gram-negative bacteria. The doses and daily regimens vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) pharmacokinetics of colistin after intraventricular administration of CMS has never been characterized. Nine patients (aged 18 to 73 years) were treated with intraventricular CMS (daily doses of 2.

Lopinavir pharmacokinetic profiles in HIV-infected patients during rifabutin-based anti-mycobacterial therapy.

Objectives: To evaluate the pharmacokinetic profile of ritonavir-boosted lopinavir in HIV-infected patients during rifabutin-based anti-mycobacterial therapy.

Patients And Methods: A longitudinal, cross-over pharmacokinetic evaluation of lopinavir with and without rifabutin in HIV-infected subjects with mycobacterial disease was done. All received lopinavir/ritonavir (400/100 mg twice a day) + an adjusted rifabutin dose of 150 mg every other day.