A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention

Defining tissue and plasma-specific prophylactic drug concentrations is central to pre-exposure prophylaxis product development for sexual transmission of HIV-1. Pharmacokinetic (PK) data from study RMP-02/MTN-006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV-1 seronegative adults was used to construct a multicompartment plasma-rectal tissue population PK model for TFV and tenofovir-diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV-1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4

Moduli Stabilisation and de Sitter String Vacua from Magnetised D7 Branes

Anomalous U(1)'s are ubiquitous in 4D chiral string models. Their presence crucially affects the process of moduli stabilisation and cannot be neglected in realistic set-ups. Their net effect in the 4D effective action is to induce a matter field dependence in the non-perturbative superpotential and a Fayet-Iliopoulos D-term. We study flux compactifications of IIB string theory in the presence of magnetised D7 branes. These give rise to anomalous U(1)'s that modify the standard moduli stabilisation procedure. We consider simple orientifold models to determine the matter field spectrum and the form of the effective field theory. We apply our results to one-modulus KKLT and multi-moduli large volume scenarios, in particular to the Calabi-Yau P^4_{[1,1,1,6,9]}. After stabilising the matter fields, the effective action for the Kahler moduli can acquire an extra positive term that can be used for de Sitter lifting with non-vanishing F- and D-terms. This provides an explicit realization of the D-term lifting proposal of hep-th/0309187.Comment: 35 pages, 1 figure. v2: Minor changes, references adde

Anti-D3 branes and moduli in non-linear supergravity

Anti-D3 branes and non-perturbative effects in flux compactifications spontaneously break supersymmetry and stabilise moduli in a metastable de Sitter vacua. The low energy 4D effective field theory description for such models would be a supergravity theory with non-linearly realised supersymmetry. Guided by string theory modular symmetry, we compute this non-linear supergravity theory, including dependence on all bulk moduli. Using either a constrained chiral superfield or a constrained vector field, the uplifting contribution to the scalar potential from the anti-D3 brane can be parameterised either as an F-term or Fayet-Iliopoulos D-term. Using again the modular symmetry, we show that 4D non-linear supergravities that descend from string theory have an enhanced protection from quantum corrections by non-renormalisation theorems. The superpotential giving rise to metastable de Sitter vacua is robust against perturbative string-loop and $\alpha'$ corrections.Comment: 33 page

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Oxypurinol pharmacokinetics and pharmacodynamics in healthy volunteers: Influence of BCRP Q141K polymorphism and patient characteristics.

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously