Concentrations of remdesivir and GS-441524 in human milk from lactating individuals diagnosed with COVID-19.

IMPACT: Findings from this study provide further reassuring evidence that infant exposure through human milk received from lactating individuals who require treatment with remdesivir is negligible.

Chinook salmon diversity contributes to fishery stability and trade-offs with mixed-stock harvest.

Variation among populations in life history and intrinsic population characteristics (i.e., population diversity) helps maintain resilience to environmental change and dampen interannual variability in ecosystem services. As a result, ecological variation, and the processes that generate it, is considered central to strategies for managing risks to ecosystems in an increasingly variable and uncertain world. However, characterizing population diversity is difficult, particularly in large and remote regions, which often prevents its formal consideration in management advice. We combined genetic stock identification of archived scale and tissue samples with state-space run-reconstruction models to estimate migration timing and annual return abundance for eight geographically and genetically distinct Chinook salmon populations within the Canadian portion of the Yukon River. We found that among-population variation in migration timing and return abundances resulted in aggregate return migrations that were 2.1 times longer and 1.4 times more stable than if they had composed a single homogeneous population. We then fit state-space spawner-recruitment models to the annual return abundances to characterize among-population diversity in intrinsic productivity and population size and their consequences for the fisheries they support. Productivity and carrying capacity varied among populations by approximately 2.4-fold (2.9 to 6.9 recruits per spawner) and three-fold (8800 to 27,000 spawners), respectively. This diversity implies an equilibrium trade-off between harvesting of the population aggregate and the conservation of individual populations whereby the harvest rate predicted to maximize aggregate harvests comes at the cost of overfishing ~40% of the populations but with a relatively low risk of extirpating the weakest ones. Our findings illustrate how population diversity in one of the largest salmon-producing river basins in the world contributes to fishery stability and food security in a region where salmon have high cultural and subsistence value. More generally, our work demonstrates the utility of molecular analyses of archived biological material for characterizing diversity in biological systems and its benefits and consequences for trade-offs in decision-making.

Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a non-inferiority randomized controlled trial study protocol.

BACKGROUND: Retrospective observational studies suggest that transmission of Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300 mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the standard 60d/300 mg course is not yet established. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed. METHODS AND DESIGN: We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150 mg/day (30d/150 mg) vs. BZN 60d/300 mg. We will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at 6 months postpartum, and follow them up with the following specific aims: Specific aim 1: to measure the effect of BZN 30d/150 mg compared to 60d/300 mg preconceptional treatment on parasitic load measured by the frequency of positive Polymerase Chain Reaction (PCR) (primary outcome) and by real-time quantitative PCR (qPCR), immediately and 10 months after treatment. Specific aim 2: to measure the frequency of serious adverse events and/or any adverse event leading to treatment interruption. TRIAL REGISTRATION: ClinicalTrials.gov . Identifier: NCT03672487 . Registered 14 September 2018.

Determination of Benznidazole in Human Dried Blood Spots by Liquid Chromatography-Mass Spectrometry to Monitor Adherence to Trypanosoma cruzi Infection Treatment in Infants and Children.

Medication adherence is critical to the effectiveness of benznidazole (BZ) therapy for the treatment of Chagas disease. Assessing BZ adherence using traditional plasma sampling methods presents numerous challenges in resource-limited settings. Dried blood spot (DBS) sampling of BZ can be used to overcome logistical barriers and provides a less invasive method for assessing BZ levels. A BZ DBS assay using liquid chromatography-tandem mass spectrometry was developed and applied to a clinical study of infants and children being treated with BZ for Trypanosoma cruzi infection in Argentina. The assay was validated over a concentration range of 9.8-5,000 ng/mL. Inter-assay and intra-assay measures ranged from -2.9% to 2.7% and 0.5% to 8.3% for accuracy and from 3.5% to 12% and 1.6% to 13.6% for precision, respectively. The mean recovery of BZ was greater than 91%. Partitioning ratios for DBSs/plasma ranged from 0.95 to 1.02. A cohort of 10 infants and six children with T. cruzi infection being treated with BZ had median BZ concentrations of 1.2 (IQR 0.29, 2.14) µg/mL with seven of 65 (11%) samples above the BZ treatment goal of 3 µg/mL for adults. The reported DBS assay is a simple and accurate method for the quantitative measurement of BZ that can be applied to facilitate urgently needed clinical studies of BZ for the treatment of Chagas disease and assess BZ adherence in resource-limited settings.

Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial.

BACKGROUND: Low/ered cholesterol is linked to aggression in some study designs. Cases/series have reported reproducible aggression increases on statins, but statins also bear mechanisms that could reduce aggression. Usual statin effects on aggression have not been characterized. METHODS: 1016 adults (692 men, 324 postmenopausal women) underwent double-blind sex-stratified randomization to placebo, simvastatin 20mg, or pravastatin 40mg (6 months). The Overt-Aggression-Scale-Modified-Aggression-Subscale (OASMa) assessed behavioral aggression. A significant sex-statin interaction was deemed to dictate sex-stratified analysis. Exploratory analyses assessed the influence of baseline-aggression, testosterone-change (men), sleep and age. RESULTS: The sex-statin interaction was significant (P=0.008). In men, statins tended to decrease aggression, significantly so on pravastatin: difference=-1.0(SE=0.49)P=0.038. Three marked outliers (OASMa-change ≥40 points) offset otherwise strong significance-vs-placebo: statins:-1.3(SE=0.38)P=0.0007; simvastatin:-1.4(SE=0.43)P=0.0011; pravastatin:-1.2(SE=0.45)P=0.0083. Age≤40 predicted greater aggression-decline on statins: difference=-1.4(SE=0.64)P=0.026. Aggression-protection was emphasized in those with low baseline aggression: age<40-and-low-baseline-aggression (N=40) statin-difference-vs-placebo=-2.4(SE=0.71)P=0.0016. Statins (especially simvastatin) lowered testosterone, and increased sleep problems. Testosterone-drop on statins predicted aggression-decline: ß=0.64(SE=0.30)P=0.034, particularly on simvastatin: ß=1.29(SE=0.49)P=0.009. Sleep-worsening on statins significantly predicted aggression-increase: ß=2.2(SE=0.55)P<0.001, particularly on simvastatin (potentially explaining two of the outliers): ß=3.3(SE=0.83)P<0.001. Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) ß=0.70(SE=0.34)P=0.039. The increase was significant, without exclusions, for women of more typical postmenopausal age (≥45): (N=304) ß=0.68(SE=0.34)P=0.048 - retaining significance with modified age-cutoffs (≥50 or ≥55). Significance was observed separately for simvastatin. The aggression-increase in women on statins was stronger in those with low baseline aggression (N=175) ß=0.84(SE=0.30)P=0.006. No statin effect on whole blood serotonin was observed; and serotonin-change did not predict aggression-change. CONCLUSION: Statin effects on aggression differed by sex and age: Statins generally decreased aggression in men; and generally increased aggression in women. Both findings were selectively prominent in participants with low baseline aggression - bearing lower change-variance, rendering an effect more readily evident. TRIAL REGISTRATION: Clinicaltrials.gov NCT00330980.

Preclinical toxicity screening of intrathecal oxytocin in rats and dogs.

BACKGROUND: Anatomic, physiologic, and behavioral studies in animals suggest that spinally released oxytocin should produce analgesia in humans and may also protect from chronic pain after injury. In this article, the authors report preclinical toxicity screening of oxytocin for intrathecal delivery. METHODS: Intrathecal oxytocin, 11 µg (6 U) or vehicle, was injected intrathecally in 24 rats, followed by frequent behavioral assessment and histologic examination of spinal contents 2 or 14 days after injection. In three dogs, a range of intrathecal oxytocin doses (18 to 550 µg in 0.5 ml) was injected followed by physiologic, biochemical, and behavioral assessments. Ten dogs were then randomized to receive five daily injections of intrathecal oxytocin, 550 µg in 0.5 ml, or vehicle with similar assessments and, necropsy and histologic analysis were conducted 2 days later. RESULTS: In rats, intrathecal oxytocin resulted in transient scratching and itching behaviors, without other differences from vehicle. There was no behavioral, gross anatomic, or histologic evidence of neurotoxicity. Dose ranging in dogs suggested mild effects on motor tone, blood pressure, and heart rate at the 550 µg dose. Repeated boluses in dogs did not produce behavioral, biochemical, neurological, gross anatomic, or histologic evidence of neurotoxicity. CONCLUSIONS: Substances, including natural neurotransmitters, may be toxic when administered in pharmacologic doses in the spinal cord. This preclinical toxicity screen in two species suggests that bolus injections of oxytocin in concentrations up to 1,100 µg/ml are unlikely to cause neurotoxicity. The authors also support cautious clinical application of intrathecal oxytocin under regulatory supervision.

Selective formation of secondary amides via the copper-catalyzed cross-coupling of alkylboronic acids with primary amides.

For the first time, a general catalytic procedure for the cross-coupling of primary amides and alkylboronic acids is demonstrated. The key to the success of this reaction was the identification of a mild base (NaOSiMe3) and oxidant (di-tert-butyl peroxide) to promote the copper-catalyzed reaction in high yield. This transformation provides a facile, high-yielding method for the monoalkylation of amides.

Determination of efavirenz in human dried blood spots by reversed-phase high-performance liquid chromatography with UV detection.

BACKGROUND: Previously published methods for determination of efavirenz (EFV) in human dried blood spots (DBS) use costly and complex liquid chromatography/mass spectrometry. We describe the validation and evaluation of a simple and inexpensive high-performance liquid chromatography method for EFV quantification in human DBS and dried plasma spots (DPS), using ultraviolet detection appropriate for resource-limited settings. METHODS: One hundred microliters of heparinized whole blood or plasma were spotted onto blood collection cards, dried, punched, and eluted. Eluates are injected onto a C-18 reversed phase high-performance liquid chromatography column. EFV is separated isocratically using a potassium phosphate and acetonitrile mobile phase. Ultraviolet detection is at 245 nm. Quantitation is by use of external calibration standards. Following validation, the method was evaluated using whole blood and plasma from HIV-positive patients undergoing EFV therapy. RESULTS: Mean recovery of drug from DBS is 91.5%. The method is linear over the validated concentration range of 0.3125-20.0 µg/mL. A good correlation (Spearman r = 0.96) between paired plasma and DBS EFV concentrations from the clinical samples was observed, and hematocrit level was not found to be a significant determinant of the EFV DBS level. The mean observed C DBS/C plasma ratio was 0.68. A good correlation (Spearman r = 0.96) between paired plasma and DPS EFV concentrations from the clinical samples was observed. The mean percent deviation of DPS samples from plasma samples is 1.68%. CONCLUSIONS: Dried whole blood spot or dried plasma spot sampling is well suited for monitoring EFV therapy in resource-limited settings, particularly when high sensitivity is not essential.

Stability of dilute oral morphine solution for neonatal abstinence syndrome.

BACKGROUND: Oral morphine is a recommended option for the treatment of neonatal abstinence syndrome (NAS). Commercially available oral morphine solution products in the United States are not formulated in concentrations appropriate for use in neonates. OBJECTIVE: To test the stability of a diluted oral morphine solution for treatment of NAS. METHODS: Ethanol-free morphine 2 mg/mL oral solution was diluted to 0.4 mg/mL with sterile water and stored in a light protected container at room temperature (20°C-25°C). The change in morphine concentration over time was measured by liquid chromatography mass spectrometry with simultaneous ultraviolet diode array detection. RESULTS: : The test morphine solution retained 107% of its original concentration after 60 days. CONCLUSION: Extemporaneously prepared 0.4 mg/mL oral morphine solution is suitable for use in the treatment of NAS as a potentially safer alternative to opium-containing agents.

Etravirine in CSF is highly protein bound.

OBJECTIVES: Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL). METHODS: Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8-2000 (plasma) and 0.78-200 (CSF) ng/mL. RESULTS: Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens. CONCLUSIONS: Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.

Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration.

OBJECTIVES: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC(90)). METHODS: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. RESULTS: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC(90) for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. CONCLUSIONS: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana.

BACKGROUND: Pharmacokinetic data for lopinavir in late pregnancy and in breastfeeding are limited, and no data for abacavir in breast milk are available. METHODS: Women in the Mma Bana Study initiated HAART from 18 to 34 weeks of gestation. We determined trough plasma and whole breast milk concentrations of lopinavir (LPV), abacavir (ABC), nevirapine (NVP), lamivudine (3TC) and zidovudine (ZDV) among separate subsets of pregnant and breastfeeding women, and in plasma of exposed infants. Lopinavir was measured 1 month after starting HAART or 1 month postpartum, and other drugs were measured 1 month postpartum. RESULTS: Sampling occurred a median of 14 h (range 11-17) from last maternal drug ingestion. Although 50% higher median LPV levels were seen in postpartum than antepartum plasma (8.29 µg/ml versus 5.51 µg/ml; P = 0.02), antepartum levels with standard LPV dosing were therapeutic for all women (> 1.0 µg/ml). Very low LPV levels (< 0.25 µg/ml) were detected in breast milk. Median ABC levels in breast milk were 85% of those in plasma (0.057 µg/ml versus 0.067 µg/ml). Breast milk concentrations of NVP and 3TC were 27% and 74% of plasma levels, respectively. At these trough maternal time points, only NVP was detectable in potentially inhibitory levels in breastfeeding infants, and most infants had non-detectable levels of LPV, ABC, ZDV and 3TC via maternal breast milk. CONCLUSIONS: Standard LPV dosing achieved therapeutic levels in pregnancy and no appreciable concentrations in breast milk. ABC is detectable in breast milk at similar concentrations to plasma, but does not result in appreciable infant exposure.

Therapeutic amprenavir concentrations in cerebrospinal fluid.

Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = -0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC50 for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.

Lower than expected maraviroc concentrations in cerebrospinal fluid exceed the wild-type CC chemokine receptor 5-tropic HIV-1 50% inhibitory concentration.

To measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations. Total maraviroc was measured by reverse-phase high-performance liquid chromatography with tandem mass spectrometry, whereas ultrafiltration was used for unbound maraviroc. Maraviroc was detected in all nine CSF/plasma pairs with a median CSF total concentration of 2.4 ng/ml. CSF concentrations exceeded the 50% inhibitory concentration of wild-type CC chemokine receptor 5-tropic HIV-1 in all specimens. CSF concentrations are lower than expected based on plasma concentrations and physicochemical characteristics. Unbound maraviroc plasma concentrations may be informative in estimating concentrations in CSF.

Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir.

BACKGROUND: Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study's objective was to determine tenofovir's penetration into cerebrospinal fluid (CSF). METHODS: CNS HIV Antiretroviral Therapy Effects Research is a multicenter observational study to determine the effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL. RESULTS: One hundred eighty-three participants (age 44 ± 8 years; 83 ± 32 kg; 33 females; CSF protein 44 ± 16 mg/dL) had plasma and CSF samples drawn 12.2 ± 6.9 and 11 ± 7.8 hours post dose, respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL [interquartile range (IQR) 47-153 ng/mL] and 5.5 ng/mL (IQR 2.7-11.3 ng/mL), respectively. Thirty-four of 231 plasma (14.7%) and 9 of 77 CSF samples (11.7%) were below detection. CSF to plasma concentration ratio from paired samples was 0.057 (IQR 0.03-0.1; n = 38). Median CSF to wild-type 50% inhibitory concentration ratio was 0.48 (IQR 0.24-0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type 50% inhibitory concentration. More subjects had detectable CSF HIV with lower (≤ 7 ng/mL) versus higher (>7 ng/mL) CSF tenofovir concentrations (29% versus 9%; P = 0.05). CONCLUSIONS: Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF.

A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men.

RATIONALE: The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones. OBJECTIVES: We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin. METHODS: In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo. RESULTS: Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels. CONCLUSION: These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.

Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children.

OBJECTIVE: Lopinavir/ritonavir (Kaletra) is first-line therapy for pediatric HIV infection. In clinical practice, Kaletra tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children. DESIGN: This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had 2 separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets. METHODS: PK blood samples were drawn at 0 (predose), 1, 2, 4, 6, 8, and 12 hours postdose. Lopinavir and ritonavir plasma concentrations measured by high-performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance. Wilcoxon signed-rank tests compared PK values between crushed and whole tablets. RESULTS: Twelve children, median age of 13 years (10-16 years), took 550/138 mg·m(-2) per day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC after crushed and whole tablets were 92 mg·hr·L(-1) and 144 mg·hr·L(-1), respectively, with an AUC ratio of 0.55 (P = 0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg·hr·L(-1) and 13.3 mg·hr·L(-1), respectively, with an AUC ratio of 0.53 (P = 0.006). CONCLUSIONS: Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.

Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life.

BACKGROUND: There are no previous data describing nelfinavir and lamivudine pharmacokinetics in neonates treated with weight-band dosing regimens. DESIGN: Pharmacokinetic study of nelfinavir and lamivudine pharmacokinetics in infants during the first 2 weeks of life treated with weight-band dosing regimens. METHODS: Intensive 12-hour pharmacokinetic profiles were performed between either days 4-7 or days 10-14 of life in 26 Brazilian infants. RESULTS: Pharmacokinetic data were obtained from 26 infants who received median (range) per kg doses of 58.8 (48.4-79.0) mg/kg for nelfinavir and 2.0 (1.5-3.2) mg/kg for lamivudine. Median nelfinavir 12-hour AUC (AUC0-12) was 25.5 (1.7-183.5) µg*h/mL and median 12-hour concentration (C12h) was 1.09 (<0.04-14.44) µg/mL. AUC0-12 was less than 15 µg*h/mL (the 10% for adults) in 12 infants (46%). Median lamivudine AUC0-12 was 7.8 (2.7-15.6) µg*h/mL and median C12h was 0.23 (<0.04-0.74) µg/mL. CONCLUSIONS: : Lamivudine pharmacokinetic parameters observed in this study were consistent with those seen in other studies of neonates. While median nelfinavir AUC and C12h in these neonates were above the exposure targets, interindividual variability in nelfinavir exposure was large and nelfinavir exposure failed to meet the exposure targets in 46% of infants.