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. BsAbs are generally more complex to investigate and develop than monoclonal antibodies, because they recognize at least 2 different antigens. Understanding their relative affinities to each target is crucial for determining their mechanism of action and efficacy. Moreover, the presence or absence of an Fc region determines, in part, their in vivo stability, distribution, and half-life. This study summarizes several PK and PD aspects that are specific for BsAbs and are important for the success of these new drugs. We emphasize previous PK/PD studies that have been fundamental for the correct prediction of appropriate dosages and schedules of these new drugs in clinical trials or for defining which drugs may take advantage of individualized and standardized drug monitoring for improved efficacy and safety.

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. Multiple analyses of patient-derived PK data have identified various factors influencing the clearance of mAbs. These factors include the presence of antidrug antibodies, low serum albumin, high serum levels of C-reactive protein, high body weight, and gender differences among others. The same clearance processes involved in systemic clearance after intravenous administration are also involved in local first-pass catabolism after subcutaneous administration of mAbs. Therapeutic drug monitoring has been proposed as a way to understand and respond to the variability in clinical response and remission. For both classes of mAbs with anti-inflammatory and antitumor effects, dose-guided optimization based on the measurement of serum concentrations in individual patients could be the next step for a personalized and targeted mAb therapy.

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. METHODS: This is a two-arm, open-label, pharmacokinetic, randomised study conducted in Burkina Faso between May 2013 and December 2015. Enrolled patients were randomised to receive either 150 mg RBT EOD (arm A, 9 subjects) or 300 mg RBT EOD (arm B, 7 subjects), both associated with LPV/r taken twice daily. RBT plasma concentrations were evaluated after 2 weeks of combined HIV and TB treatment. Samples were collected just before drug ingestion and at 1, 2, 3, 4, 6, 8, and 12 h after drug ingestion to measure plasma drug concentration using an HPLC-MS/MS assay. RESULTS: The Cmax and AUC0-12h medians in arm A (Cmax = 296 ng/mL, IQR: 205-45; AUC0-12h = 2528 ng.h/mL, IQR: 1684-2735) were lower than those in arm B (Cmax = 600 ng/mL, IQR: 403-717; AUC0-12h = 4042.5 ng.h/mL, IQR: 3469-5761), with a statistically significant difference in AUC0-12h (p = 0.044) but not in Cmax (p = 0.313). No significant differences were observed in Tmax (3 h versus 4 h). Five patients had a Cmax below the plasma therapeutic limit (< 300 ng/mL) in the 150 mg RBT arm, while the Cmax was above this threshold for all patients in the 300 mg RBT arm. Additionally, at 48 h after drug ingestion, all patients had a mycobacterial minimum inhibitory concentration (MIC) above the limit (> 64 ng/mL) in the 300 mg RBT arm, while 4/9 patients had such values in the 150 mg RBT arm. CONCLUSION: This study confirmed that the 150 mg dose of rifabutin ingested EOD in combination with LPV/r is inadequate and could lead to selection of rifamycin-resistant mycobacteria. TRIAL REGISTRATION: PACTR201310000629390, 28th October 2013.

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. Study inclusion criteria were that the patients were between 18 and 60 years of age, HIV-1 infected with pulmonary tuberculosis confirmed or suspected. Subsequent blood samples for pharmacokinetic monitoring were collected at 1, 2, 3, 4, 6, 8 and 12 h after combined drug ingestion for plasma drug monitoring using HPLC/MS assays. RESULTS: The medians LPV Cmax and Tmax were respectively, 20 µg/mL and 4 h for the RBT 150 mg group (arm A) and 7.7 µg/mL and 3 h for the RBT 300 mg group (arm B). The AUC0-12 of LPV was 111.8 µg h/mL in patients belonging to arm A versus 69.9 µg/mL for those in arm B (p = 0.313). The C0 of LPV was lower than 4 µg/mL in three patients receiving RBT 300 mg. Of note, the RTV plasma concentrations were nearly halved among patients on RBT 300 mg compared to those on lower RBT doses. The AUC0-12 of RTV in arm A was 12.7 µg h/mL versus 6.6 µg h/ml in arm B (p = 0.313). CONCLUSION: In our study, the pharmacokinetic of LPV and RTV was found to be highly variable when coadministrated with RBT 150 mg or 300 mg three times per week. There is a need for specific large study to verify clinical and virological effects of this variation, especially when coadministrated with RBT of 300 mg TPW, and to prevent viral resistance in response to under-dosing of LPV. Trial registration PACTR201310000629390. Registered 28 October 2013, http://www.pactr.org/.

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 ß-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. After incubation and washings, substrate solution was added and absorbance was read at 492 nm. ATLG concentrations in samples were determined by interpolation from a standard curve (range: 200-0.095 ng/mL), prepared by diluting a known amount of ATLG in phosphate-buffered saline (PBS). Low, medium, and high-quality control concentrations were 1.56, 6.25, and 25 ng/mL, respectively. This method was developed and validated within the acceptance criteria in compliance with the Guidelines for a biological method validation: the sensitivity of the method was 0.095 ng/mL. We analyzed serum samples from 14 children with ß-Thalassemia who received ATLG (Grafalon) at a dose of 10 mg/kg administered as intravenous (IV) infusion on days -5, -4, and -3 before HSCT (day 0). Blood sampling for PK evaluation was performed on days -5, -4, and -3 before and after drug infusion; and then from day -2 to +56. RESULTS: The median total ATLG levels pre-IVand post-IV were 0 and 118 mcg/mL on day -5; 85.9 and 199.2 mcg/mL on day -4; 153 and 270.9 mcg/mL on day -3, respectively. The median PK values of CL was 0.0029 (range: 0.0028-0.0057) L·kg·d, Vd was 0.088 (range: 0.025-0.448) L/kg and t1/2 was 20.2 (range: 5.8-50.2) days. CONCLUSIONS: These data suggest that given the marked interindividual variability of total ATLG disposition, the development of a validated ELISA method and the possibility to measure PK parameters in paediatric populations are essential steps to optimize drug therapeutic regimens.

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. The pharmacokinetic parameters included peak plasma concentration (Cmax), time corresponding to Cmax (tmax), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) or to the last sampling time assessment (AUC0-36), the elimination rate constant (ke), and the terminal half-life (t1/2). Safety was measured by pre- and post-treatment specific biochemical investigations, physical examination, electrocardiogram, occurrence of adverse events, and any information on patients' withdrawal. RESULTS: The geometric mean ratio Test/Reference (90% confidence interval) for levosulpiride was 103.0% (95.8-110.8) for AUC0-36, 103.6% (95.9-111.9) for AUC0-∞, and 104.3% (94.9-114.6) for Cmax. ke and t1/2 were 0.07 (SD: 0.02) and 9 hours (8-12) for both the formulations. Clearance (L/h) was 29.6 (±13.5) and 30.7 (±14.2) for the test and the reference product, respectively. CONCLUSIONS: Because the acceptance criteria required by the drug regulatory agency (European Medicines Agency, EMA) for bioequivalence prescribe limits of 80%-120% for untransformed data and 80%-125% for "ln" transformed data, we can confirm that the 2 formulations are bioequivalent, in terms of the rate and extent of absorption.

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. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD.

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. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion. METHODS: One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 µg/mL or of ropivacaine 0.2% + sufentanil 0.75 µg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses. RESULTS: The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups. CONCLUSIONS: Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic.

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. METHODS: The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale <4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay. RESULTS: Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h(-1)·kg(-1); the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively). CONCLUSIONS: This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.

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. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated. RESULTS: DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found. CONCLUSIONS: In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.

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. RESULTS: An association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G_C_C_A_C and A_T_T_G_T) that did not prove to be related with plasma morphine and M3G/M6G concentration. CONCLUSIONS: By considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy.

Rituximab in children with resistant idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m(2) intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, -12% [95% confidence interval, -73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

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. They can also guide the clinician in tailoring the delivery of antibiotics to suit an individual patient's needs. Model-informed precision dosing, such as Bayesian forecasting dosing software (which incorporates PK/PD population models), may be utilized to optimize antibiotic exposure in neonatal populations. Consequently, optimizing the antibiotic dose and exposure in each newborn requires expertise in different fields. It drives the collaboration of physicians together with lab technicians and quantitative clinical pharmacologists.

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 2.61 to 10.44 mg). Colistin concentrations were measured using a selective high-performance liquid chromatography (HPLC) assay. The population pharmacokinetics analysis was performed with the P-Pharm program. The pharmacokinetics of colistin could be best described by the one-compartment model. The estimated values (means ± standard deviations) of apparent CSF total clearance (CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and terminal half-life (t(1/2λ)) were 0.033 ± 0.014 liter/h and 7.8 ± 3.2 h, respectively, and the average time to the peak concentration was 3.7 ± 0.9 h. A positive correlation between CL/Fm and the amount of CSF drained (range 40 to 300 ml) was observed. When CMS was administered at doses of ≥5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 µg/ml, and measured values of trough concentration (C(trough)) ranged between 2.0 and 9.7 µg/ml. Microbiological cure was observed in 8/9 patients. Intraventricular administration of CMS at doses of ≥5.22 mg per day was appropriate in our patients, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent.

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. Twelve-hour lopinavir pharmacokinetic sampling occurred at 2 weeks (T1) and 6 weeks (T2) after starting combined therapy and 10 weeks after completion of adjusted rifabutin (T3). Plasma was assayed using an HPLC method; lopinavir plasma concentration-time data were analysed using non-compartmental methods. RESULTS: In 10 patients with complete lopinavir curves at T1, T2 and T3 pharmacokinetic values were, respectively: AUC(0-12), 187.5, 161.8 and 121.1 µg ·â€Šh/mL; C(trough), 13.2, 10.0 and 7.7 µg/mL; C(max), 18.7, 15.9 and 13.3 µg/mL; and apparent oral clearance (CL/F), 0.035, 0.037 and 0.045 L/h/kg. Lopinavir C(trough) and AUC(0-12) were significantly higher at T1 compared with T3 while CL/F remained unchanged throughout. Combined treatment was well tolerated and none of the patients experienced moderate to severe lopinavir-related adverse events. CONCLUSIONS: Lopinavir serum concentrations are not reduced when the drug is administered together with an adjusted dose of 150 mg of rifabutin every other day.

Systemic exposure to rifampicin in patients with tuberculosis and advanced HIV disease during highly active antiretroviral therapy in Burkina Faso.

OBJECTIVES: Low plasma concentrations of rifampicin, an essential antituberculosis drug, have been reported particularly among HIV co-infected persons. In a prospective, longitudinal study we measured rifampicin systemic exposure at different timepoints during highly active antiretroviral therapy (HAART). PATIENTS AND METHODS: From May 2006 to April 2007, 16 tuberculosis (TB)/HIV co-infected patients were enrolled in Ouagadougou, Burkina Faso. All patients received fixed dose combinations of rifampicin, isoniazid, pyrazinamide and ethambutol under direct observation and HAART, consisting of a fixed dose combination of stavudine, lamivudine and nevirapine. Rifampicin concentrations during the dosing interval were determined by HPLC at three different timepoints: (i) after 2 weeks of TB therapy and before starting HIV therapy (T0); (ii) after 4 weeks of combined therapy (T1); and (iii) after 10 weeks of combined therapy (T2). RESULTS: The median values of the area under the curve (AUC(0-24)) of rifampicin increased by 39% at T1 (15.69 µg ·â€Šh/mL; P = 0.01) and by 83% at T2 (20.65 µg ·â€Šh/mL; P = 0.001) compared with T0 (11.28 µg ·â€Šh/mL). Similar variations were observed for the median C(max) at T0 (2.24 µg/mL) compared with T2 (2.83 µg/mL; P = 0.003). However, none of the subjects had C(max) levels >8 µg/mL at either T0 or T2. CONCLUSIONS: Rifampicin systemic exposure increased during combined TB and HIV therapy, possibly due to increased drug absorption or decreased oral clearance, but remained invariably low in this population. Studies to define the C(max) rifampicin concentrations, which are associated with a significantly increased risk of treatment failure, are urgently warranted.

Morphine metabolism, transport and brain disposition.

The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

Relationship between pharmacokinetic profile of subcutaneously administered alemtuzumab and clinical response in patients with chronic lymphocytic leukemia.

Alemtuzumab serum levels and clinical response after subcutaneous administration (10 mg 3 times/week for six weeks) have been explored in 29 chronic lymphocytic leukemia patients receiving the monoclonal antibody as consolidation. Serum concentrations after each administration gradually increased during the first week and more markedly during weeks 2 and 3, approaching the steady-state at week 6. Absorption continued slowly through the tissues for about 2-3 weeks after the last administration, starting to decrease thereafter. Difference between Responders and Non-responders was statistically significant: maximal concentration (Cmax) was 1.69 µg/mL vs. 0.44 µg/mL; concentration before subcutaneous administration (Cpre-dose) on day 15 was 0.7 vs. 0.21 µg/mL, area under curve (AUC0-12h) was 11.09 vs. 2.26 µgxh/mL for Responders and Non-responders, respectively. Higher systemic exposure to alemtuzumab correlated with a better clinical response and minimal residual disease. Results suggest that an adjusted schedule according to serum level could improve clinical outcome of patients receiving subcutaneous alemtuzumab.

Therapeutic monitoring and variability of atazanavir in HIV-infected patients, with and without HCV coinfection, receiving boosted or unboosted regimens.

BACKGROUND: Adequate plasma trough concentrations (Ctrough) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection. METHODS: We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 µg/mL, based on the proposed therapeutic range (0.15-0.85 µg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV-, HIV+/HCV+, and HIV+/HCV+ with cirrhosis. RESULTS: In the whole study population, we observed a large variability and found suboptimal Ctrough levels (<0.15 µg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) µg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median Ctrough of 0.70 (0.43-1.0) µg/mL, with no statistical difference when compared with HIV+/HCV- infected patients. For the 400ATV OD (n=90) dosage regimen, the total median ATV Ctrough was 0.40 (0.23-1.0) µg/mL. In this group, we found a statistically significant difference between HIV+/HCV- and HIV+/HCV+-infected patients: median Ctrough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) µg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the Ctrough median value was 0.42 (0.13-0.75) µg/mL, and there was a significant difference when compared with HIV patients without coinfection. CONCLUSIONS: Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIV-infected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.